Improvement of Na+-K+ ATPase Activity and Gene Expression Associated with Glomerular Ultrastructural Protection in Diabetic Nephropathy by Acacia senegal: Role of Oxidative Stress Disturbances / Mejora de la actividad Na+-K+ ATPasa y la Expresión Génica Asociada con la Protección Ultraestructural Glomerular en la Nefropatía Diabética por Acacia senegal: Papel de las Alteraciones del Estrés Oxidativo

SUMMARY: This study assessed the effects of Acacia Senegal (AS) combined with insulin on Na+/K+-ATPase (NKA) activity and mRNA expression, serum glucose, renal function, and oxidative stress in a rat model of diabetic nephropathy (DN). Sixty rats were equally divided into six groups: normal control, normal+AS, diabetic (DM), DM+insulin, DM+AS, and DM+insulin+AS groups. Diabetes mellitus (type 1) was induced by a single injection of streptozotocin (65 mg/kg), and insulin and AS treatments were carried until rats were culled at the end of week 12. Serum glucose and creatinine levels, hemoglobin A1c (HbA1c) were measured. Renal homogenate levels of NKA activity and gene expression, malondialdehyde, superoxide dismutase (SOD), catalase and reduced glutathione (GSH) were evaluated as well as kidney tissue histology and ultrastructure. Diabetes caused glomerular damage and modulation of blood and tissue levels of creatinine, glucose, HbA1c, malondialdehyde, NKA activity and gene expression, SOD, catalase and GSH, which were significantly (p<0.05) treated with AS, insulin, and insulin plus AS. However, AS+insulin treatments were more effective. In conclusion, combined administration of AS with insulin to rats with DN decreased NKA activity and gene expression as well as oxidative stress, and improved glycemic state and renal structure and function.

Este estudio evaluó los efectos de Acacia senegal (AS) combinada con insulina sobre la actividad Na+/K+- ATPasa (NKA) y la expresión de ARNm, la glucosa sérica, la función renal y el estrés oxidativo en un modelo de nefropatía diabética (ND) en ratas. Sesenta ratas se dividieron equitativamente en seis grupos: control normal, normal+AS, diabética (DM), DM+insulina, DM+AS y DM+insulina+AS. La diabetes mellitus (tipo 1) se indujo mediante una única inyección de estreptozotocina (65 mg/kg), y los tratamientos con insulina y AS se llevaron a cabo hasta que las ratas fueron sacrificadas al final de la semana 12. Se midieron niveles séricos de glucosa y creatinina, hemoglobina A1c (HbA1c). Se evaluaron los niveles de homogeneizado renal de actividad NKA y expresión génica, malondialdehído, superóxido dismutasa (SOD), catalasa y glutatión reducido (GSH), así como la histología y ultraestructura del tejido renal. La diabetes causó daño glomerular y modulación de los niveles sanguíneos y tisulares de creatinina, glucosa, HbA1c, malondialdehído, actividad y expresión génica de NKA, SOD, catalasa y GSH, los cuales fueron tratados significativamente (p<0,05) con AS, insulina e insulina más AS. Sin embargo, los tratamientos con AS+insulina fueron más efectivos. En conclusión, la administración combinada de AS con insulina a ratas con DN disminuyó la actividad de NKA y la expresión genética, así como el estrés oxidativo, y mejoró el estado glucémico y la estructura y función renal.

Renal protective effect of ellipticine against streptozotocin induced diabetic nephropathy in rats via suppression of oxidative stress and inflammatory mediator

Purpose: Diabetes mellitus is a serious health problem worldwide, and diabetic nephropathy is the complication. The diabetic nephropathy considerably enhances the oxidative stress, glycation, lipid parameters and inflammatory reaction. Ellipticine has potent free radical scavenging and anti-inflammatory effect. Methods: In the current study, our objectives were to thoroughly examine the renal protective effects of ellipticine in a rat model of streptozotocin (STZ)-induced diabetic nephropathy (DN) and to elucidate the underlying mechanisms involved. For the induction of diabetic nephropathy, streptozotocin (50 mg/kg) was used, and rats were separated into groups and given varying doses of ellipticine (2.5, 5 and 7.5 mg/kg). The body weight, and renal weight were estimated. The inflammatory cytokines, renal biomarkers, inflammatory antioxidant, and urine parameters were estimated. Results: Result showed that ellipticine considerably enhanced the body weight and reduced the renal tissue weight. Ellipticine treatment significantly (P < 0.001) repressed the level of blood urea nitrogen, serum creatinine, uric acid, blood glucose and altered the lipid parameters. Ellipticine significantly (P < 0.001) repressed the level of malonaldehyde and boosted the glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Ellipticine treatment significantly (P < 0.001) reduced the inflammatory cytokines and inflammatory mediators. Conclusions: Ellipticine could be a renal protective drug via attenuating the inflammatory reaction, fibrosis and oxidative stress in streptozotocin induced rats.

Rastreamento da doença renal do diabetes na atenção primária à saúde / Screening for diabetes kidney disease in primary health care

A Doença Renal do Diabetes (DRD) é assintomática nos estágios iniciais da doença, e por esse motivo, a maioria dos pacientes é diagnosticada somente quando já apresenta várias complicações. O objetivo deste estudo foi avaliar se o rastreio da DRD está sendo realizado de maneira adequada em pacientes com diabetes mellitus tipo 2 (DM2) atendidos na atenção primária à saúde (APS) do Sistema Único de Saúde. Foi realizado um estudo transversal, com duração de cinco meses, na APS dos municípios de Bernardino de Campos e Salto Grande, SP. Os critérios de inclusão foram: diagnóstico de DM2, idade > 18 anos, e ser acompanhado nas unidades participantes do estudo. Um total de 1093 atenderam aos critérios de inclusão e aceitaram participar do estudo. Foi verificado que 398 (36,4%) dos pacientes nunca realizaram os exames de albumina urinária e creatinina, e não tiveram calculados a relação albumina/creatinina em amostra de urina com o cálculo da taxa de filtração glomerular (TFG) estimada pela CKD-EPI a partir da creatinina sérica; 401 (36,7%) dos pacientes realizaram estes exames e tiveram estes índices calculados nos últimos 12 meses. Estes 401 pacientes realizaram estes exames e cálculos de rastreio da DRD uma vez a cada 12 meses nos últimos 5 anos. Os demais pacientes (294; 26,9%) realizaram somente exame de creatinina sérica nos últimos 12 meses. Os resultados demonstraram que o rastreamento da DRD não está sendo realizado de maneira adequada na maioria dos pacientes (AU).

Diabetes Kidney Disease (DRD) is asymptomatic in the early stages of the disease, and for this reason, most patients are diagnosed only when they already have several complications. The aim of this study was to assess whether DRD screening is being carried out properly in patients with type 2 diabetes mellitus (DM2) treated in primary health care (PHC) of the Unified Health System. A cross-sectional study was carried out, lasting five months, in the PHC of the municipalities of Bernardino de Campos and Salto Grande, SP. Inclusion criteria were: diagnosis of DM2, age > 18 years, and being monitored in the units participating in the study. A total of 1093 met the inclusion criteria and agreed to participate in the study. It was found that 398 (36.4%) of the patients had never performed urine albumin and creatinine tests, and they did not calculate the albumin/creatinine ratio in a urine sample, together with the calculation of the glomerular filtration rate (GFR) estimated by CKD-EPI from serum creatinine; in contrast, 401 (36.7%) of the patients underwent these exams and had these indexes calculated in the last 12 months. These 401 patients had these DRD screening tests and calculations performed once every 12 months for the last 5 years. Os demais pacientes (294; 26,9%) realizaram somente exame de creatinina sérica nos últimos 12 meses. Os resultados demonstraram que o rastreamento da DRD não está sendo realizado de maneira adequada na maioria dos pacientes (AU).

Alpha-kinase1 promotes tubular injury and interstitial inflammation in diabetic nephropathy by canonical pyroptosis pathway

BACKGROUND: Alpha-kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1ß in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1ß and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. METHODS: Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1ß, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1ß and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. RESULTS: The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1ß in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1ß, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. CONCLUSIONS: Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.

Experimental model of nephropathy associated with diabetes mellitus in mice

Purpose: Nontransmissible chronic diseases, such as diabetes mellitus (DM) and nephropathy, affect a significant portion of the population, often treated due to injuries that require healing and regeneration. To create an experimental model of associated comorbidities, for healing and regeneration studies, protocols for induction of nephropathy by ischemia and reperfusion (I/R) and induction of DM by injection of streptozotocin (STZ) were associated. Methods: Sixty-four mice (Mus musculus), female, adult, Swiss strain, weighing approximately 20 g, were divided into four groups: G1: control (n = 24), G2: nephropathy group (N) (n = 7), G3, DM (n = 9), and G4: N+DM (n = 24). Arteriovenous stenosis (I/R) of the left kidney was performed as the first protocol. The animals received a hyperlipidemic diet for 7 days after the injection of STZ (150 mg/kg, via i.p.) and an aqueous glucose solution (10%) for 24 h. The animals in the G3 and G4 groups were observed for 14 days before receiving the diet and STZ. The evolution of nephropathy was observed using a urine test strip and the DM, through the analysis of blood glucose with a reagent strip on a digital monitor. Results: The ischemic induction protocols of nephropathy and DM with STZ, associated, were sustainable, low-cost, and without deaths. There were alterations compatible with initial renal alterations, in the first 14 days, such as increased urinary density, pH alteration, presence of glucose, proteins and leukocytes, when compared to the control group. DM was confirmed by the presence of hyperglycemia 7 days after induction and its evolution after 14 days. The animals in the G4 group showed constant weight loss when compared to the other groups. It was possible to observe morphological alterations in the kidneys submitted to I/R, regarding coloration, during surgery and after the end of the observation period, in the volume and size of the left kidney, when compared to the contralateral kidney. Conclusion: It was possible to induce nephropathy and DM associated in the same animal, in a simple way, confirmed with rapid tests, without losses, providing a basis for future studies.

Visualization analysis of research hotspots in pathogenesis of diabetic nephropathy in China / 中华预防医学杂志

The aim of this study is to analyze the research hotspots and development trends in the field of pathogenesis of diabetic nephropathy in China from 2013 to 2022. Based on China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China Science and Technology Journal Database, China Biology Medicine disc, Web of Science core collection and PubMed database, the related literatures in the field of pathogenesis of diabetic nephropathy in China from 2013 to 2022, were retrieved to establish the database, and the VOSviewer software was used for bibliometric analysis. A total of 1 664 Chinese and 2 149 English literatures are included in this study. The scientific research results from 2013 to 2022 have shown an overall increasing trend. The research hotspots in the field of pathogenesis of diabetic nephropathy in China are mainly concentrated in Podocytes, Oxidative stress, Inflammation, Renal fibrosis, Urine protein, etc. The frontier hotspots in this field include Biomarkers, Nrf2, Gut microbiota, NLRP3 inflammasome, Apoptosis, MicroRNA, etc. Through visual analysis, the research hotspots and frontier trends of the pathogenesis of diabetic nephropathy in China can be visually presented, and then provide new ideas and directions for the further in-depth research on the pathogenesis of diabetic nephropathy.

Eucommia lignans alleviate the progression of diabetic nephropathy through mediating the AR/Nrf2/HO-1/AMPK axis in vivo and in vitro / 中国天然药物

Lignans derived from Eucommia ulmoides Oliver (Eucommia lignans) inhibit the progression of inflammatory diseases, while their effect on the progression of diabetic nephropathy (DN) remained unclear. This work was designed to assess the function of Eucommia lignans in DN. The major constituents of Eucommia lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia lignans (200, 100, and 50 mg·kg-1) were used in model animals to evaluate their renal function changes. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia lignans to evaluate whether Eucommia lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia lignans significantly attenuated the progression of DN in vivo. Eucommia lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the levels of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia lignans. Meanwhile, knockdown of AR exerted similar therapeutic effect of Eucommia lignans on DN progression, and AR overexpression reversed the effect of Eucommia lignans. Eucommia lignans alleviated renal injury through the AR/Nrf2/HO-1/AMPK axis. Thus, these findings might provide evidence for the use of Eucommia lignans in treating DN.

Evaluation of Renal Impairment in Patients with Diabetic Kidney Disease by Integrated Chinese and Western Medicine / 中国结合医学杂志

OBJECTIVE@#To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine.@*METHODS@#Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients.@*RESULTS@#Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD.@*CONCLUSIONS@#Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).

1, 25-(OH)2-VitD3 attenuates renal tubulointerstitial fibrosis in diabetic kidney disease by inhibiting Snail1-SMAD3/SMAD4 complex formation / 细胞与分子免疫学杂志

Objective To investigate the effect of 1, 25-(OH)2-VitD3 (VitD3) on renal tubuleinterstitial fibrosis in diabetic kidney disease. Methods NRK-52E renal tubular epithelial cells were divided into control group (5.5 mmol/L glucose medium treatment), high glucose group (25 mmol/L glucose medium treatment) and high glucose with added VitD3 group (25 mmol/L glucose medium combined with 10-8 mmol/L VitD3). The mRNA and protein expression of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in NRK-52E cells were detected by real-time quantitative PCR and Western blot analysis respectively. The expression and localization of Snail1, SMAD3 and SMAD4 were detected by immunofluorescence cytochemical staining. The binding of Snail1 with SMAD3/SMAD4 complex to the promoter of Coxsackie-adenovirus receptor (CAR) was detected by chromatin immunoprecipitation. The interaction among Snail1, SMAD3/SMAD4 and E-cadherin were detected by luciferase assay. Small interfering RNA (siRNA) was used to inhibit the expression of Snail1 and SMAD4, and the expression of mRNA of E-cadherin was detected by real-time quantitative PCR. SD rats were randomly divided into control group, DKD group and VitD3-treated group. DKD model was established by injection of streptozotocin (STZ) in DKD group and VitD3-treated group. After DKD modeling, VitD3-treated group was given VitD3 (60 ng/kg) intragastric administration. Control group and DKD group were given normal saline intragastric administration. In the DKD group and VitD3-treated group, insulin (1-2 U/kg) was injected subcutaneously to control blood glucose for 8 weeks. The mRNA and protein levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissues were detected by real-time quantitative PCR and Western blot analysis respectively. Immunohistochemistry was used to detect the expression and localization of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissue. Results Compared with the control group, the mRNA and protein expressions of Snail1, SMAD3, SMAD4 and α-SMA in NRK-52E cells cultured with high glucose and in DKD renal tissues were up-regulated, while E-cadherin expression was down-regulated. After the intervention of VitD3, the expression levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in the DKD model improved to be close to those in the control group. Chromatin immunoprecipitation showed that Snail1 and SMAD3/SMAD4 bound to CAR promoter IV, while VitD3 prevented Snail1 and SMAD3/SMAD4 from binding to CAR promoter IV. Luciferase assay confirmed the interaction among Snail1, SMAD3/SMAD4 and E-cadherin. After the mRNA of Snail1 and SMAD4 was inhibited by siRNA, the expression of E-cadherin induced by high glucose was up-regulated. Conclusion VitD3 could inhibit the formation of Snail1-SMAD3/SMAD4 complex and alleviate the renal tubulointerstitial fibrosis in DKD.

Network Meta-analysis of Qi-supplementing and Yin-nourishing Chinese patent medicines in treatment of early diabetic nephropathy / 中国中药杂志

This study aimed to evaluate the efficacy of Qi-supplementing and Yin-nourishing Chinese patent medicine in the treatment of early diabetic nephropathy(DN) by network Meta-analysis to explore the Chinese patent medicine with optimal efficacy and provide references for preventing renal deterioration and delaying the progression of early DN. Eight databases, including CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science, were searched for clinical randomized controlled trial(RCT) of Qi-supplementing and Yin-nourishing Chinese patent medicines in the treatment of early DN. After the literature mee-ting the inclusion criteria was screened, the quality of the literature was evaluated using the Cochrane risk-of-bias tool, and network Meta-analysis was performed using the BUGSnet package in R 4.2.1. Seventy-two research articles with a sample size of 6 344 cases were included, involving eight Chinese patent medicines and seven outcome indicators. The results of the network Meta-analysis showed that(1)in terms of improving urinary albumin excretion rate(UAER), Chinese patent medicines combined with conventional treatment were superior to conventional treatment, and Qiyao Xiaoke Capsules + conventional treatment was optimal.(2)In terms of reducing serum crea-tinine(Scr), Bailing Capsules + conventional treatment had superior efficacy.(3)In terms of reducing 24-hour urine total protein(24hUTP), Shenyan Kangfu Tablets + conventional treatment and Jinshuibao Capsules + conventional treatment had equivalent efficacy, and Shenyan Kangfu Tablets + conventional treatment was superior.(4)In terms of improving fasting blood glucose(FBG), Shenyan Kangfu Tablets + conventional treatment had superior efficacy.(5)In terms of improving total cholesterol(TC), Qiyao Xiaoke Capsules +conventional treatment had superior efficacy.(6)In terms of reducing triglyceride(TG), Bailing Capsules + conventional treatment had superior efficacy.(7)In terms of safety, the occurrence of adverse reactions was reported in seven interventions, but due to the large clinical heterogeneity, the quantitative analysis could not be performed. Overall, Qi-supplementing and Yin-nourishing Chinese patent medicines combined with conventional treatment were superior to conventional treatment alone in the treatment of early DN. The results showed that Qi-supplementing and Yin-nourishing Chinese patent medicines combined with conventional treatment had good clinical efficacy, and they could significantly reduce renal function indicators such as UAER, Scr, and 24hUTP, and reduce blood sugar and blood lipid, which can provide evidence-based support for the treatment of early DN. However, due to the differences in the quantity and quality of the included research articles, large-sample, multi-center, high-quality studies are still needed for further verification.

Network Meta-analysis of efficacy of Chinese patent medicine in treatment of inflammatory response in diabetic nephropathy / 中国中药杂志

This study aimed to evaluate the efficacy and safety of various Chinese patent medicines in the treatment of inflammatory response in diabetic nephropathy(DN) based on network Meta-analysis. Randomized controlled trial(RCT) of oral Chinese patent medicines for improving inflammatory response in patients with DN was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, Web of Science, and other databases from database inception to October 2022. All investigators independently screened the literature, extracted data, and evaluated the quality. Stata 16.0 software and RevMan 5.4.1 were used to analyze the data of the literature that met the quality standards. Finally, 53 RCTs were included, involving 6 Chinese patent medicines. The total sample size was 4 891 cases, including 2 449 cases in the test group and 2 442 cases in the control group. The network Meta-analysis showed that(1) in terms of reducing TNF-α, the top 3 optimal interventions according to the surface under the cumulative ranking curve(SUCRA) were Shenshuaining Capsules/Granules/Tablets + conventional western medicine, Jinshuibao Capsules + conventional western medicine, and Niaoduqing Granules + conventional western medicine.(2) In terms of reducing hs-CRP, the top 3 optimal interventions according to SUCRA were Bailing Capsules + conventional western medicine, Tripterygium Glycosides Tablets + conventional western medicine, and Shenshuaining Capsules/Granules/Tablets + conventional western medicine.(3) In terms of reducing IL-6, the top 3 optimal interventions according to SUCRA were Bailing Capsules + conventional western medicine, Tripterygium Glycosides Tablets + conventional western medicine, and Jinshuibao Capsules + conventional western medicine.(4) In terms of reducing UAER, the top 3 optimal interventions according to SUCRA were Shenshuaining Capsules/Granules/Tablets + conventional western medicine, Huangkui Capsules + conventional western medicine, and Jinshuibao Capsules + conventional western medicine.(5) In terms of reducing Scr, the top 3 optimal interventions according to SUCRA were Jinshuibao Capsules + conventional western medicine, Niaoduqing Granules + conventional wes-tern medicine, and Tripterygium Glycosides Tablets + conventional western medicine.(6) In terms of reducing BUN, the first 3 optimal interventions according to SUCRA were Niaoduqing Granules + conventional western medicine, Tripterygium Glycosides Tablets + conventional western medicine, and Huangkui Capsules + conventional western medicine.(7) In terms of improving the clinical total effective rate, the first 3 optimal interventions according to SUCRA were Jinshuibao Capsules + conventional western medicine, Niaoduqing Granu-les + conventional western medicine, and Huangkui Capsules + conventional western medicine. The results showed that the combination of western medicine and Chinese patent medicine could reduce the expression of serum inflammatory factors TNF-α, hs-CRP, and IL-6 and inhibit the inflammatory response. The combination of western medicine and Chinese patent medicine was superior to western medicine alone in reducing Scr, BUN, and UAER, and improving the total effective rate of treatment. Due to the limitation of the quantity and quality of literature included, the above conclusions need to be validated by more high-quality studies.

Effects and mechanisms of total flavones of Abelmoschus manihot in attenuating diabetic tubulopathy by targeting endoplasmic reticulum stress-induced cell apoptosis / 中国中药杂志

Renal tubular injury in patients with diabetic kidney disease(DKD) may be accompanied by glomerular and microvascular diseases. It plays a critical role in the progression of renal damage in DKD, and is now known as diabetic tubulopathy(DT). To explore the multi-targeted therapeutic effects and pharmacological mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese medicine for treating kidney disease, in attenuating DT, the authors randomly divided all rats into four groups: a normal control group(normal group), a DT model group(model group), a DT model+TFA-treated group(TFA group) and a DT model+rosiglitazone(ROS)-treated group(ROS group). The DT rat model was established based on the DKD rat model by means of integrated measures. After successful modeling, the rats in the four groups were continuously given double-distilled water, TFA suspension, and ROS suspension, respectively by gavage every day. After 6 weeks of treatment, all rats were sacrificed, and the samples of their urine, blood, and kidneys were collected. The effects of TFA and ROS on various indicators related to urine and blood biochemistry, renal tubular injury, renal tubular epithelial cell apoptosis and endoplasmic reticulum stress(ERS), as well as the activation of the protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic translation initiation factor 2α(eIF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP) signaling pathway in the kidney of the DT model rats were investigated. The results indicated that hypertrophy of renal tubular epithelial cells, renal tubular hyperplasia and occlusion, as well as interstitial extracellular matrix and collagen deposition occurred in the DT model rats. Moreover, significant changes were found in the expression degree and the protein expression level of renal tubular injury markers. In addition, there was an abnormal increase in tubular urine proteins. After TFA or ROS treatment, urine protein, the characteristics of renal tubular injury, renal tubular epithelial cell apoptosis and ERS, as well as the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney of the DT model rats were improved to varying degrees. Therein, TFA was superior to ROS in affecting the pathological changes in renal tubule/interstitium. In short, with the DT model rats, this study demonstrated that TFA could attenuate DT by multiple targets through inhibiting renal tubular ERS-induced cell apoptosis in vivo, and its effect and mechanism were related to suppressing the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney. These findings provided preliminary pharmacological evidence for the application of TFA in the clinical treatment of DT.

Effects and mechanisms of total flavones of Abelmoschus manihot in improving insulin resistance and podocyte epithelial-mesenchymal transition in diabetic kidney disease based on IRS1/PI3K/Akt pathway / 中国中药杂志

This study aimed to explore the effects and mechanisms of total flavones of Abelmoschus manihot(TFA), the extracts from traditional Chinese medicine indicated for kidney diseases, on insulin resistance(IR) and podocyte epithelial-mesenchymal transition(EMT) in diabetic kidney disease(DKD), and further to reveal the scientific connotation. Thirty-two rats were randomly divided into a normal group, a model group, a TFA group, and a rosiglitazone(ROS) group. The modified DKD model was induced in rats by methods including high-fat diet feeding, unilateral nephrectomy, and streptozotocin(STZ) intraperitoneal injection. After modeling, the rats in the four groups were given double-distilled water, TFA suspension, and ROS suspension correspondingly by gavage every day. At the end of the 8th week of drug administration, all rats were sacrificed, and the samples of urine, blood, and kidney tissues were collected. The parameters and indicators related to IR and podocyte EMT in the DKD model rats were examined and observed, including the general condition, body weight(BW) and kidney weight(KW), the biochemical parameters and IR indicators, the protein expression levels of the key signaling molecules and structural molecules of slit diaphragm in the renal insulin receptor substrate(IRS) 1/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(Akt) pathway, foot process form and glomerular basement membrane(GBM) thickness, the expression of the marked molecules and structural molecules of slit diaphragm in podocyte EMT, and glomerular histomorphological characteristics. The results showed that for the DKD model rats, both TFA and ROS could improve the general condition, some biochemical parameters, renal appearance, and KW. The ameliorative effects of TFA and ROS were equivalent on BW, urinary albumin(UAlb)/urinary creatinine(UCr), serum creatinine(Scr), triglyceride(TG), and KW. Secondly, they could both improve IR indicators, and ROS was superior to TFA in improving fast insulin(FIN) and homeostasis model assessment of insulin resistance(HOMA-IR). Thirdly, they could both improve the protein expression levels of the key signaling molecules in the IRS1/PI3K/Akt pathway and glomerulosclerosis in varying degrees, and their ameliorative effects were similar. Finally, both could improve podocyte injury and EMT, and TFA was superior to ROS. In conclusion, this study suggested that podocyte EMT and glomerulosclerosis could be induced by IR and the decreased activation of the IRS1/PI3K/Akt pathway in the kidney in DKD. Similar to ROS, the effects of TFA in inhibiting podocyte EMT in DKD were related to inducing the activation of the IRS1/PI3K/Akt pathway and improving IR, which could be one of the scientific connotations of TFA against DKD. This study provides preliminary pharmacological evidence for the development and application of TFA in the field of diabetic complications.

Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway / 中国中药杂志

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1β(IL-1β) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1β and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

Role of TGF-β/Smad signaling pathway in diabetic kidney disease and research progress of traditional Chinese medicine intervention / 中国中药杂志

Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-β(TGF-β)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-β/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-β/Smad signaling pathway. This study clarified the mechanism of TGF-β/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-β/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.

Role of Brain Angiotensin-II in Development of Experimental Diabetic Nephropathy in Wistar Rats

Abstract The renin-angiotensin-aldosterone system (RAAS) plays a key role in diabetic nephropathy (DN). Angiotensin-II secreted during the RAAS pathway increases nephropathy. It stimulates oxidative stress which can quench nitric oxide. Reduced nitric oxide level aggravates Ang-II-induced vasoconstriction. Ang-II has also emerged as a central mediator of the glomerular hemodynamic changes that are associated with renal injury. Deletion of ACE2 is also noted due to increased Ang-II level which leads to the development of DN. We hypothesize that nephropathy caused by Ang-II in the periphery may be controlled by brain RAAS. ACE inhibitors and ARBs may show the renoprotective effect when administered through ICV without crossing the blood-brain barrier. DN was observed after 8 weeks of diabetes induction through alloxan. Administration of captopril and valsartan once and in combined therapy for 2 weeks, significantly reduced urine output, blood urea nitrogen, total protein in the urine, serum cholesterol, serum creatinine, serum triglycerides, and kidney/body weight ratio as compared to diabetic control rats. Further, combination therapy significantly increased the body weight and serum nitrate level as compared to diabetic control animals. However, increased ACE2 levels in the brain may reduce the sympathetic outflow and might have decreased the peripheral activity of Ang-II which shows beneficial effects in DN.

Recomendaciones para evaluar la tasa de filtrado glomerular menor de 60 ml/min/1, 73 m2 en pacientes con enfermedad renal y diabetes mellitus / Recommendations to evaluate the glomerular filtration rate below 60 ml/min/1. 73 m2 in patients with kidney disease and diabetes

Diagnosticar, clasificar y estadificar la enfermedad renal en pacientes con diabetes mellitus (DM) es un desafío tanto para los médicos de atención primaria como para los especialistas, porque no existe método en la práctica clínica que evalúe la tasa de filtrado glomerular (TFG) en forma precisa. Para evaluar la función renal en enfermedad renal crónica (ERC) con menos de 60 ml/min/1.73m2 , correspondiente a los estadios 3, 4 y 5 de la clasificación actual, los métodos disponibles en los laboratorios clínicos son de limitada exactitud. En este trabajo se desarrollarán las condiciones que debería cumplir un marcador ideal, las dificultades que ofrece la evaluación de la creatinina, la medición de la TFG, así como las ventajas y limitaciones de las recomendaciones del uso de fórmulas para su determinación, y el algoritmo actual para estimar función renal. Conclusiones: actualmente, a pesar de las limitaciones, se recomienda el empleo de fórmulas para la estimación de la TFG, sobre todo en TFG menor a 60 ml/min/1.73 m2. Es un desafío, para un futuro mediato, desarrollar mejores recursos para su evaluación.

To diagnose,classify and stage diabetic kidney disease in patients with diabetes mellitus is a challenge in clinical practice for both primary care physicians and specialists because there is no method in clinical practice that evaluates accurately the glomerular filtration rate (GFR). This challenge is due to difficulties in evaluating kidney function in stages of chronic kidney disease (CKD) below 60 ml/min/1.73m2 corresponding to stages 3, 4 and 5 of the classification, because the available tools in clinical laboratories are of limited accuracy. This work explores the conditions that an ideal marker should meet, the difficulties offered by the evaluation of serum creatinine, the measurement of the glomerular filtration rate (GFR) as well as the advantages and limitations of the recommendations of the use of formulas for its determination and the current algorithm to estimate renal function. Conclusions: currently, despite the limitations, the use of formulas for the diagnosis of renal function is recommended, especially in GFR below 60 ml/min/1.73 m2. It is a challenge for the near future to develop better tools for the evaluation of TGF.

Acacia senegal inhibits diabetic nephropathy ultrastructure alteration and renal biomarkers changes in rats / Acacia senegal inhibe la alteración de la ultraestructura de la nefropatía diabética y los cambios en los biomarcadores renales en rata

SUMMARY: Diabetic nephropathy (DN) is the most common complication of diabetes. Several studies have been done in a trial to protect against this problem at the ultrastructure level. This study investigates the protective effect of oral administration of Acacia senegal (AS) against the development of DN. Sixty male albino rats were randomly divided into six groups: control, Acacia senegal control, Diabetic untreated, diabetic insulin-treated, Diabetic AS treated, and Diabetic insulin and AS combined treated groups. Plasma glucose, HbA1c, serum Albumin, creatinine, urine creatinine was measured using specific kits. Determinations of creatinine clearance and blood pressure were done. The renal tissues of both kidneys were prepared to investigate under both light (LM) and electron microscope (EM). Ultrastructure examination of renal rats tissue of diabetic untreated rats showed the destruction of the glomerular basement membrane and endothelial cells together with hemorrhage in glomerular capsules (Bowman's capsules). On the other side, both LM and EM revealed improving the endothelial cells and the other glomerular capsules structures, especially with the combined treated group, which confirmed the improvement of the biochemical investigation in the study. In conclusion, from the present study, using the oral AS together with SC insulin could be protected against the development of DN.

RESUMEN: La nefropatía diabética (ND) es la complicación más común de la diabetes. Se han realizado varios estudios de ensayo para abordar esta dificultad a nivel de ultraestructura. Este estudio investiga el efecto protector de la administración oral de Acacia senegal (AS) contra el desarrollo de la ND. Se dividieron sesenta ratas albinas machos aleatoriamente en seis grupos: control, control de Acacia senegal, diabéticos no tratados, diabéticos tratados con insulina, diabéticos tratados con AS y grupos tratados con compuesto de insulina diabética + AS. Se midieron utilizando kits específicos, glucosa plasmática, HbA1c, albúmina sérica, creatinina en sangre y en orina. Se registraron la creatinina y la presión arterial. Los tejidos renales de ambos riñones se prepararon para investigar tanto con microscopio óptico (MO) como electrónico (ME). El examen de la ultraestructura del tejido renal de ratas diabéticas no tratadas mostró la destrucción de la membrana basal glomerular y las células endoteliales junto con hemorragia en las cápsulas glomerulares (cápsulas de Bowman). Por otro lado, tanto MO como ME revelaron una mejora de las células endoteliales y las estructuras capsulares glomerulares, en el grupo tratado con el compuesto, lo que confirmó la mejora de la investigación bioquímica. En conclusión, el uso de AS oral en combinación con insulina podría proteger contra el desarrollo de ND.

Análisis geográfico de nefropatía diabética e insuficiencia renal en el primer nivel de atención, IMSS 2019 / Geographic analysis of diabetic nephropathy and renal insufficiency in the primary care, IMSS 2019

Introducción: en un contexto donde la prevalencia de diabetes mellitus e hipertensión arterial ha aumentado significativamente en años recientes, las enfermedades renales adquieren importancia por la potencial demanda de atención especializada y de recursos en salud que requieren. Objetivo: analizar la distribución geográfica de la nefropatía diabética (ND) y la insuficiencia renal (IR) con base en las consultas otorgadas en unidades de primer nivel del Instituto Mexicano del Seguro Social (IMSS) durante 2019, para identificar las unidades médicas con mayor carga de atención. Material y métodos: estudio ecológico-exploratorio en el que se estimaron indicadores por cada mil derechohabientes en relación a las consultas otorgadas por ND e IR según la ocasión de servicio, la unidad médica familiar (UMF) de primer nivel y la representación. Se utilizó estadística espacial para analizar dichos indicadores. Resultados: el 45% de las consultas otorgadas fue por ND y el 52.4% por IR. La mayor carga por ND se registró en la UMF No. 50 de Cd. Juárez (Chihuahua) y en la No. 49 Gabino Barreda (Veracruz Sur), con 1.7 consultas de primera vez y 148.3 subsecuentes por mil derechohabientes, respectivamente. Mientras que en la UMF No. 40 Manlio Fabio Altamirano y No. 25 Cotaxtla, en Veracruz Norte, la mayor carga fue por IR, con 4.9 consultas de primera vez y 134.2 subsecuentes por mil derechohabientes, respectivamente. Conclusiones: los resultados podrían contribuir al fortalecimiento de las unidades médicas que así lo requieran y en la distribución eficiente de los recursos disponibles para atender la demanda de servicios de salud de ND e IR en el IMSS

Background: In a context where the prevalence of Diabetes Mellitus and Hypertension has increased significantly in recent years, kidney diseases become important for the potential demand for specialized health care and resources required. Objective: To analyze the geographical distribution of Diabetic Nephropathy (DN) and Renal Insufficiency (RI) based on the medical consultations given in first-level units of IMSS during 2019, to identify the medical units with the highest burden of care. Material and methods: Ecological-exploratory study in which indicators were estimated for every thousand persons in relation to medical consultations given by ND and RI according to service time, first-level medical unit (UMF) and representation to analyze the magnitude and geographic distribution at the national level. Results: 45% of medical consultations were by ND and 52.4% by RI. The highest burden per DN was registered in UMF No. 50 Cd. Juarez (Chihuahua) and No. 49 Gabino Barreda (Veracruz Sur), with 1.7 first-time medical consultations and 148.3 subsequent medical consultations per 1,000 persons, respectively. While in UMF No. 40 Manlio Fabio Altamirano and No. 25 Cotaxtla, in Veracruz Norte, the highest burden was for RI, with 4.9 first-time medical consultations and 134.2 subsequent medical consultations per 1000 persons, respectively. Conclusions: The results could contribute to strengthening of medical units where it is necessary and the efficient allocation of resources available to meet the demand for health services of ND and RI in IMSS.

The A allele of the rs759853 single nucleotide polymorphism in the AKR1B1 gene confers risk for diabetic kidney disease in patients with type 2 diabetes from a Brazilian population

ABSTRACT Objective: The AKR1B1 gene encodes an enzyme that catalyzes the reduction of glucose into sorbitol. Chronic hyperglycemia in patients with diabetes mellitus (DM) leads to increased AKR1B1 affinity for glucose and, consequently, sorbitol accumulation. Elevated sorbitol increases oxidative stress, which is one of the main pathways related to chronic complications of diabetes, including diabetic kidney disease (DKD). Accordingly, some studies have suggested the rs759853 polymorphism in the AKR1B1 gene is associated with DKD; however, findings are still contradictory. The aim was to investigate the association of the rs759853 polymorphism in the AKR1B1 gene and DKD. Materials and methods: The sample comprised 695 patients with type 2 DM (T2DM) and DKD (cases) and 310 patients with T2DM of more than 10 years' duration, but no DKD (controls). The polymorphism was genotyped by real-time PCR. Results: Allelic and genotype frequencies of this polymorphism did not differ significantly between groups. However, the A/A genotype was associated with risk for DKD after adjustment for gender, triglycerides, BMI, presence of hypertension and diabetic retinopathy, and duration of DM, under both recessive (P = 0.048) and additive (P = 0.037) inheritance models. Conclusion: Our data suggest an association between the AKR1B1 rs759853A/A genotype and risk for DKD in Brazilians T2DM patients.