The circ_0003928/miR-31-5p/MAPK6 cascade affects high glucose-induced inflammatory response, fibrosis and oxidative stress in HK-2 cells.

BACKGROUND: Diabetic nephropathy (DN) is a severe diabetic complication disorder. Circular RNAs (circRNAs) actively participate in DN pathogenesis. In this report, we sought to define a new mechanism of circ_0003928 in regulating high glucose (HG)-induced HK-2 cells. METHODS: To construct a DN cell model, we treated HK-2 cells with HG. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. The inflammatory cytokines were quantified by ELISA. Protein analysis was performed by immunoblotting, and mRNA expression was detected by quantitative PCR. The circ_0003928/miR-31-5p and miR-31-5p/MAPK6 relationships were validated by RNA pull-down and luciferase assays. RESULTS: HG promoted HK-2 cell apoptosis, fibrosis and oxidative stress. Circ_0003928 and MAPK6 levels were enhanced and miR-31-5p level was decreased in HK-2 cells after HG treatment. Circ_0003928 disruption promoted cell growth and inhibited apoptosis, inflammatory response, fibrosis and oxidative stress in HG-induced HK-2 cells. Circ_0003928 targeted miR-31-5p, and MAPK6 was a target of miR-31-5p. Circ_0003928 regulated MAPK6 expression through miR-31-5p. The functions of circ_0003928 disruption in HG-induced HK-2 cells were reversed by miR-31-5p downregulation or MAPK6 upregulation. CONCLUSION: Circ_0003928 exerts regulatory impacts on HG-induced apoptosis, inflammation, fibrosis and oxidative stress in human HK-2 cells by the miR-31-5p/MAPK6 axis.

No Differences in Kidney Function Decline Between People With Type 2 Diabetes Starting a Sodium-Glucose Cotransporter 2 Inhibitor or a Glucagon-like Peptide-1 Receptor Agonist: A Real-world Retrospective Comparative Observational Study.

PURPOSE: Diabetic nephropathy represents the leading cause of end-stage kidney disease in developed countries. Cardiovascular outcome trials have found that in participants who received a glucagon-like peptide-1 receptor agonist (GLP1RA) and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), the risk of incidence and progression of diabetic nephropathy in type 2 diabetes mellitus was reduced. The aim of this study was to compare the decline in estimated glomerular filtration rate (eGFR) among people taking a GLP1RA with that among people taking an SGLT2i in a real-world setting. METHODS: Data for 478 patients with type 2 diabetes mellitus who initiated therapy with a GLP1RA (n = 254) or an SGLT2i (n = 224) between January 1, 2018 and December 31, 2021 were extracted. The primary outcome was any reduction ≥30% in eGFR after the start of therapy. Weight loss and drug discontinuation were also assessed. FINDINGS: Over a median follow-up of 24 months, an eGFR reduction ≥30% occurred in 34 of 254 patients (13.4%) starting a GLP1RA and in 26 of 223 patients (11.6%) starting an SGLT2i (hazard ratio = 0.89; 95% CI, 0.54-1.49; P = 0.67). Median eGFR change over the whole follow-up was similar between groups (SGLT2i: median, -2 mL/min/1.73 m2; 25th, 75th percentile, -13, 8 mL/min/1.73 m2; GLP1RA: median, 0 mL/min/1.73 m2; 25th, 75th percentile, -10, 7 mL/min/1.73 m2; P = 0.54). No worsening of kidney function was observed, even when considering the ratio eGFR mean. The value of eGFR at baseline indicated a statistically significant indirect correlation with the observed absolute value of eGFR change over the follow-up (ρ = -0.36; P < 0.001). The difference in eGFR changes over time observed by eGFR categories was statistically significant (P = 0.0001) in both treatment groups. No significant differences in weight loss and drug discontinuations were observed between groups. IMPLICATIONS: Although acting on different molecular mechanisms, both GLP1RA and SGLT2i might have similar effects on eGFR decline in diabetes, as suggested by the results of the present study conducted in a real-world setting. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Tirzepatide alleviates oxidative stress and inflammation in diabetic nephropathy via IL-17 signaling pathway.

Oxidative stress (OS) and inflammation play essential roles in the development of diabetic nephropathy (DN). Tirzepatide (TZP) has a protective effect in diabetes. However, its underlying mechanism in DN remains unclear. DN model mice were induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg), followed by administration of different doses of TZP (3 and 10 nmol/kg) via intraperitoneal injection for 8 weeks. The effects of TZP on DN were evaluated by detecting DN-related biochemical indicators, kidney histopathology, apoptosis, OS, and inflammation levels. Additionally, to further reveal the potential mechanism, we investigated the role of TZP in modulating the IL-17 pathway. TZP reduced serum creatinine (sCR), blood urea nitrogen (BUN), and advanced glycosylation end products (AGEs) levels, while simultaneously promoting insulin secretion in diabetic mice. Additionally, TZP attenuated tubular and glomerular injury and reduced renal apoptosis levels. Further studies found that TZP increased the levels of SOD and CAT, and decreased MDA. Meanwhile, TZP also reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in both mouse serum and kidney homogenates. TZP effectively inhibited the IL-17 pathway, and subsequent intervention with an IL-17 pathway agonist (IL-17A) reversed the suppressive effects of TZP on OS and inflammation. TZP can improve DN by inhibiting OS and inflammation through the suppression of the IL-17 pathway.

Ferroptosis and secondary nephrosis. / é“æ­»äº¡ä¸Žç»§å‘æ€§è‚¾è„ç— .

Secondary nephrosis is a series of chronic kidney diseases secondary to other underlying diseases, mainly manifesting as structural and functional abnormalities of the kidneys and metabolic disorders. It is one of the important causes of end-stage renal disease, with high morbidity and significant harm. Iron is an essential metal element in human cells, and ferroptosis is a non-traditional form of iron-dependent cell death, and its main mechanisms include iron accumulation, lipid metabolism disorders, abnormal amino acid metabolism, and damage to the antioxidant system. Recently studies have found that ferroptosis is involved in the occurrence and progression of secondary nephrosis, and the mechanism of ferroptosis in different secondary nephrosis vary. Therefore, an in-depth and systematic understanding of the association between ferroptosis and secondary nephrosis, as well as their specific regulatory mechanisms, can provide a theoretical basis for the diagnosis, prevention, treatment, and prognosis assessment of secondary nephrosis, laying the foundation for exploring new clinical therapeutic targets for secondary nephrosis.

Value of DUSP6 in peripheral blood mononuclear cells in predicting adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy. / å¤–å‘¨è¡€å•ä¸ªæ ¸ç»†èƒžä¸­DUSP6é¢„è­¦ç³–å°¿ç— è‚¾ç— è ¹è†œé€æžåŽä¸è‰¯å¿ƒè¡€ç®¡äº‹ä»¶çš„ä»·å€¼.

OBJECTIVES: Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. METHODS: A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. RESULTS: By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all P<0.05). DUSP6 was negatively correlated with serum albumin levels (r=-0.271, P=0.002) and positively correlated with dialysis duration (rs=0.406, P<0.001) and high-sensitivity C-reactive protein (rs=0.367, P<0.001). Multiple linear regression analysis revealed that dialysis duration and high-sensitivity C-reactive protein were independently correlated with DUSP6 levels (both P<0.05). The cumulative incidence of adverse cardiovascular events was higher in the high-level DUSP6 group than in the low-level DUSP6 group (46.67% vs 7.81%, P<0.001). Cox regression analysis indicated that low serum albumin levels (HR=0.836, 95% CI 0.778 to 0.899), high high-sensitivity C-reactive protein (HR=1.409, 95% CI 1.208 to 1.644), and high DUSP6 (HR=6.631, 95% CI 2.352 to 18.693) were independent risk factors for adverse cardiovascular events in peritoneal dialysis patients. CONCLUSIONS: Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events.

Preclinical antidiabetic and antioxidant effects of Erythrophleum africanum (benth.) harms in streptozotocin-induced diabetic nephropathy.

OBJECTIVES: This study investigated the antidiabetic effects of the methanolic extract of E. africanum (MEEA) stem bark on streptozotocin (STZ)-induced diabetic nephropathy (DN) in Wistar rats. METHODS: The in vitro enzyme (α-amylase) inhibitory activity of MEEA was measured using a standard procedure. Diabetic rats with fasting blood glucose above 250 mg/dL were considered diabetic and were divided into the following groups: control (distilled water-treated), diabetic-control, diabetic metformin (100 mg/kg), diabetes + MEEA (150 mg/kg), and diabetes + MEEA (300 mg/kg) via oral gavage once daily for 14 days. At the end of the experimental period, kidney tissues were collected for biochemical and histological analyses. Kidney apoptosis and marker gene expression were measured by real-time quantitative PCR. RESULTS: MEEA exhibited α-amylase inhibitory effects. MEEA significantly (p<0.05) reduced the STZ-induced increases in blood glucose, serum urea, serum creatinine, uric acid, alanine aminotransferase, alkaline phosphatase, and malondialdehyde and increased the STZ-induced decreases in superoxide dismutase, catalase, and reduced glutathione. In addition, MEEA protects against DN by significantly downregulating the mRNA expression of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response binding protein (CREB), and cFOS and upregulating B-cell lymphoma 2 (Bcl-2), suggesting that the nephroprotective ability of MEEA is due to the modulation of the cAMP/PKA/CREB/cFOS signaling pathway. Furthermore, MEEA treatment protected against histopathological alterations observed in diabetic rats. CONCLUSIONS: The data from this study suggest that MEEA modulates glucose homeostasis and inhibits redox imbalance in DN rats.

Nephroprotective effects of Aralia taibaiensis in a high-fat diet-streptozotocin rat model of diabetic nephropathy.

Diabetic nephropathy (DN) has emerged as the foremost cause of end-stage renal disease (ESRD) globally. Endoplasmic reticulum (ER) stress plays a critical role in DN progression. Triterpenoid saponin from Aralia taibaiensis (sAT) has been reported to possess anti-diabetic and anti-oxidant effects. The aim of this study was to examine the influence of sAT on DN treatment and elucidate potential underlying mechanisms. A high-fat diet (HFD) and Streptozotocin (STZ) were employed to induce DN in male Sprague Dawley (SD) rats which were subsequently treated with varying concentrations of sAT for 8 weeks. Our findings reveal that different doses of sAT significantly mitigated hyperglycemia, reduced urinary albumin excretion, and decreased plasma creatinine and blood urea nitrogen levels in DN rats. Moreover, sAT administration improved body weight, alleviated renal fibrosis and histopathological changes in the diabetic kidneys. Notably, sAT treatment partially restored increased Bax expression and decreased Bcl-2 expression. Additionally, sAT inhibited ER stress-related proteins, including GRP78, p-PERK, ATF4 and CHOP in kidneys of DN rats. These results suggest that sAT ameliorated experimental diabetic nephropathy, at least in part, through ER stress pathway. These findings provide a scientific basis for the potential development of sAT as a therapeutic agent for DN treatment.

Research progress on Alpinia oxyphylla in the treatment of diabetic nephropathy.

Diabetic nephropathy (DN) constitutes a major microvascular complication of diabetes and is a primary cause of mortality in diabetic individuals. With the global rise in diabetes, DN has become an urgent health issue. Currently, there is no definitive cure for DN. Alpinia oxyphylla, a Chinese herbal medicine traditionally used, exhibits a wide range of pharmacological effects and is frequently used in the prevention and management of DN. This paper offers an extensive review of the biological mechanisms by which A. oxyphylla delivers therapeutic advantages in DN management. These mechanisms include activating podocyte autophagy, regulating non-coding RNA, modulating gut microbiota, alleviating lipotoxicity, counteracting oxidative stress, and diminishing inflammatory responses, underscoring the therapeutic potential of A. oxyphylla in DN treatment.

Linggui Zhugan Decoction Improves High Glucose-Induced Autophagy in Podocytes.

Objective To explore the influence of Linggui Zhugan Decoction (LGZGD) on high glucose induced podocyte autophagy Methods LGZGD containing serum were prepared by intragastric administation of 4.2 g·kg-1 (low dose), 8.4 g·kg-1 (medium dose), and 12.6 g·kg-1 (high dose) LGZGD into SD rats respectively. MPC5 and AB8/13 cells were treated with 60 mmol/L glucose to establish diabetic nephropathy podocyte model in vitro. Podocytes, MPC5 and AB8.13, were divided into control group, high glucose group, low dose LGZGD group, medium dose LGZGD group, and high dose LGZGD group, respectively. For the three LGZGD groups, before LGZGD intervention, podocytes were treated with 60 mmol/L glucose for 3 days. After treated with LGZGD containing serum, cells were collected to analyze cell migration using Transwell assay, proliferation using CCK8, apoptosis and cell cycle using flow cytometry,, autophagosome formation using transmission electron microscopy, and expression levels of Beclin-1, Atg5, LC3II/I, and P62 proteins using western blot.Results Compared with the control group, the proliferation and migration of MPC5 and AB8.13 cells in high glucose group showed slightly decreased, whereas these parameters restored after intervention with low and medium concentrations of LGZGD, with the medium dose LGZGD having the best effect. Flow cytometry analysis showed that the medium dose LGZGD group had a lower apoptosis rate (P < 0.05) and higher survival rate (P > 0.05) compared to the high dose group. High glucose arrested podocytes in G1 phase, whereas LGZGD shifted podocytes from being predominant in G1 phase to increasing into G2. High dose LGZGD significanly reduced increased autophagosome formation due to high glucose in both podocytes (P < 0.05). Western blot analysis showed that Beclin-1, Atg5, LC3Ⅱ/Ⅰ, and P62 expressions were increased in MPC5 cells treated with high glucose, and reversed after adminstration of low and medium doses of LGZGD (P < 0.05). Conclusion LGZGD reduced apoptosis and enhanced autophagy in high glucose treated podocytes via regulating Beclin-1/LC3II/I/Atg5 expression.

Molecular mechanisms of diabetic nephropathy: A narrative review.

Diabetic nephropathy (DN) is the predominant secondary nephropathy resulting in global end-stage renal disease. It is attracting significant attention in both domestic and international research due to its widespread occurrence, fast advancement, and limited choices for prevention and treatment. The pathophysiology of this condition is intricate and involves multiple molecular and cellular pathways at various levels. This article provides a concise overview of the molecular processes involved in the development of DN. It discusses various factors, such as signaling pathways, cytokines, inflammatory responses, oxidative stress, cellular damage, autophagy, and epigenetics. The aim is to offer clinicians a valuable reference for DN's diagnosis, treatment, and intervention.

Application of Proteomics and Machine Learning Methods to Study the Pathogenesis of Diabetic Nephropathy and Screen Urinary Biomarkers.

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, causing significant health problems. Early diagnosis of the disease is quite inadequate. To screen urine biomarkers of DN and explore its potential mechanism, this study collected urine from 87 patients with type 2 diabetes mellitus (which will be classified into normal albuminuria, microalbuminuria, and macroalbuminuria groups) and 38 healthy subjects. Twelve individuals from each group were then randomly selected as the screening cohort for proteomics analysis and the rest as the validation cohort. The results showed that humoral immune response, complement activation, complement and coagulation cascades, renin-angiotensin system, and cell adhesion molecules were closely related to the progression of DN. Five overlapping proteins (KLK1, CSPG4, PLAU, SERPINA3, and ALB) were identified as potential biomarkers by machine learning methods. Among them, KLK1 and CSPG4 were positively correlated with the urinary albumin to creatinine ratio (UACR), and SERPINA3 was negatively correlated with the UACR, which were validated by enzyme-linked immunosorbent assay (ELISA). This study provides new insights into disease mechanisms and biomarkers for early diagnosis of DN.

Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes.

Epigenetic mechanisms are considered to contribute to diabetic nephropathy by maintaining memory of poor glycemic control during the early stages of diabetes. However, DNA methylation changes in the human kidney are poorly characterized, because of the lack of cell type-specific analysis. We examined DNA methylation in proximal tubules purified from diabetic nephropathy patients and identified differentially methylated CpG sites, given the critical role of proximal tubules in the kidney injury. Hypermethylation was observed at CpG sites annotated to genes responsible for proximal tubule functions, including gluconeogenesis, nicotinamide adenine dinucleotide synthesis, transporters of glucose, water, phosphate, and drugs, in diabetic kidneys, while genes involved in oxidative stress and the cytoskeleton exhibited demethylation. Methylation levels of CpG sites annotated to ACTN1, BCAR1, MYH9, UBE4B, AFMID, TRAF2, TXNIP, FOXO3, and HNF4A were correlated with the estimated glomerular filtration rate, while methylation of the CpG site in RUNX1 was associated with interstitial fibrosis and tubular atrophy. Hypermethylation of G6PC and HNF4A was accompanied by decreased expression in diabetic kidneys. Proximal tubule-specific hypomethylation of metabolic genes related to HNF4A observed in control kidneys was compromised in diabetic kidneys, suggesting a role for aberrant DNA methylation in the dedifferentiation process. Multiple genes with aberrant DNA methylation in diabetes overlapped genes with altered expressions in maladaptive proximal tubule cells, including transcription factors PPARA and RREB1. In conclusion, DNA methylation derangement in the proximal tubules of patients with diabetes may drive phenotypic changes, characterized by inflammatory and fibrotic features, along with impaired function in metabolism and transport.

Kidney tea [Orthosiphon aristatus (Blume) Miq.] improves diabetic nephropathy via regulating gut microbiota and ferroptosis.

Introduction: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Due to its complex pathogenesis, new therapeutic agents are urgently needed. Orthosiphon aristatus (Blume) Miq., commonly known as kidney tea, is widely used in DN treatment in China. However, the mechanisms have not been fully elucidated. Methods: We used db/db mice as the DN model and evaluated the efficacy of kidney tea in DN treatment by measuring fasting blood glucose (FBG), serum inflammatory cytokines, renal injury indicators and histopathological changes. Furthermore, 16S rDNA gene sequencing, untargeted serum metabolomics, electron microscope, ELISA, qRT-PCR, and Western blotting were performed to explore the mechanisms by which kidney tea exerted therapeutic effects. Results: Twelve polyphenols were identified from kidney tea, and its extract ameliorated FBG, inflammation and renal injury in DN mice. Moreover, kidney tea reshaped the gut microbiota, reduced the abundance of Muribaculaceae, Lachnoclostridium, Prevotellaceae_UCG-001, Corynebacterium and Akkermansia, and enriched the abundance of Alloprevotella, Blautia and Lachnospiraceae_NK4A136_group. Kidney tea altered the levels of serum metabolites in pathways such as ferroptosis, arginine biosynthesis and mTOR signaling pathway. Importantly, kidney tea improved mitochondrial damage, increased SOD activity, and decreased the levels of MDA and 4-HNE in the renal tissues of DN mice. Meanwhile, this functional tea upregulated GPX4 and FTH1 expression and downregulated ACSL4 and NCOA4 expression, indicating that it could inhibit ferroptosis in the kidneys. Conclusion: Our findings imply that kidney tea can attenuate DN development by modulating gut microbiota and ferroptosis, which presents a novel scientific rationale for the clinical application of kidney tea.

Potent anti-inflammatory and anti-apoptotic activities of electrostatically complexed C-peptide nanospheres ameliorate diabetic nephropathy.

In the present era of "Diabetic Pandemic", peptide-based therapies have generated immense interest however, are facing odds due to inevitable limitations like stability, delivery complications and off-target effects. One such promising molecule is C-peptide (CPep, 31 amino acid polypeptide with t1/2 30 min); it is a cleaved subunit of pro-insulin, well known to suppress microvascular complications in kidney but has not been able to undergo translation to the clinic till date. Herein, a polymeric CPep nano-complexes (NPX) was prepared by leveraging electrostatic interaction between in-house synthesized cationic, polyethylene carbonate (PEC) based copolymer (Mol. wt. 44,767 Da) and negatively charged CPep (Mol. wt. 3299 Da) at pH 7.4 and further evaluated in vitro and in vivo. NPX exhibited a spherical morphology with a particle size of 167 nm and zeta potential equivalent to +10.3, with 85.70 % of CPep complexation efficiency. The cellular uptake of FITC-tagged CPep NPX was 95.61 % in normal rat kidney cells, NRK-52E. Additionally, the hemocompatible NPX showed prominent cell-proliferative, anti-oxidative (1.8 folds increased GSH; 2.8 folds reduced nitrite concentration) and anti-inflammatory activity in metabolic stress induced NRK-52E cells as well. The observation was further confirmed by upregulation of anti-apoptotic protein BCl2 by 3.5 folds, and proliferative markers (ß1-integrin and EGFR) by 3.5 and 2.3 folds, respectively, compared to the high glucose treated control group. Pharmacokinetic study of NPX in Wistar rats revealed a 6.34 folds greater half-life than free CPep. In in-vivo efficacy study in STZ-induced diabetic nephropathy animal model, NPX reduced blood glucose levels and IL-6 levels significantly by 1.3 and 2.5 folds, respectively, as compared to the disease control group. The above findings suggested that NPX has tremendous potential to impart sustained release of CPep, resulting in enhanced efficacy to treat diabetes-induced nephropathy and significantly improved renal pathology.

Unleashing the pathological role of epithelial-to-mesenchymal transition in diabetic nephropathy: The intricate connection with multifaceted mechanism.

Renal epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells undergo biochemical changes and transform into mesenchymal-like cells, resulting in renal abnormalities, including fibrosis. EMT can cause diabetic nephropathy through triggering kidney fibrosis, inflammation, and functional impairment. The diverse molecular pathways that drive EMT-mediated renal fibrosis are not utterly known. Targeting key signaling pathways involved in EMT may help ameliorate diabetic nephropathy and improve renal function. In such settings, understanding precisely the complicated signaling networks is critical for developing customized therapies to intervene in EMT-mediated diabetic nephropathy.

Evaluating new biomarkers for diabetic nephropathy: Role of α2-macroglobulin, podocalyxin, α-L-fucosidase, retinol-binding protein-4, and cystatin C.

BACKGROUND: The intricate relationship between type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) presents a challenge in understanding the significance of various biomarkers in diagnosis. AIM: To elucidate the roles and diagnostic values of α2-macroglobulin (α2-MG), podocalyxin (PCX), α-L-fucosidase (AFU), retinol-binding protein-4 (RBP-4), and cystatin C (CysC) in DN. METHODS: From December 2018 to December 2020, 203 T2DM patients were enrolled in the study. Of these, 115 were diagnosed with DN (115 patients), while the remaining 88 patients were classified as non-DN. The urinary levels of α2-MG, PCX, and AFU and the serum concentrations RBP-4 and CysC were measured in conjunction with other relevant clinical indicators to evaluate their potential correlations and diagnostic utility. RESULTS: After adjustments for age and gender, significant positive correlations were observed between the biomarkers CysC, RBP-4, α2-MG/urinary creatinine (UCr), PCX/UCr, and AFU/UCr, and clinical indicators such as urinary albumin-to-creatinine ratio (UACR), serum creatinine, urea, 24-h total urine protein, and neutrophil-to-lymphocyte ratio (NLR). Conversely, these biomarkers exhibited negative correlations with the estimated glomerular filtration rate (P < 0.05). Receiver operating characteristic (ROC) curve analysis further demonstrated the diagnostic performance of these biomarkers, with UACR showcasing the highest area under the ROC curve (AUCROC) at 0.97. CONCLUSION: This study underscores the diagnostic significance of α2-MG, PCX, and AFU in the development of DN. The biomarkers RBP-4, CysC, PCX, AFU, and α2-MG provide promising diagnostic insights, while UACR is the most potent diagnostic biomarker in assessing DN.

New perspectives in the management of diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is also associated with increased risk for cardiovascular events. Until recently, strict glycemic control and blockade of the renin-angiotensin system (RAS) constituted the mainstay of treatment of DN. However, randomized controlled trials showed that sodium-glucose cotransporter 2 inhibitors further reduce the progression of DN. Therefore, these agents are recommended in all patients with DN regardless of DN stage and HbA1c levels. Moreover, additional blockade of the RAS with finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, was also shown to prevent both the decline of renal function and cardiovascular events in this population. Finally, promising preliminary findings suggest that glucagon-like peptide 1 receptor agonists might also exert reno- and cardioprotective effects in patients with DN. Hopefully, this knowledge will improve the outcomes of this high-risk group of patients.

Pathological mechanism of immune disorders in diabetic kidney disease and intervention strategies.

Diabetic kidney disease is one of the most severe chronic microvascular complications of diabetes and a primary cause of end-stage renal disease. Clinical studies have shown that renal inflammation is a key factor determining kidney damage during diabetes. With the development of immunological technology, many studies have shown that diabetic nephropathy is an immune complex disease, and that most patients have immune dysfunction. However, the immune response associated with diabetic nephropathy and autoimmune kidney disease, or caused by ischemia or infection with acute renal injury, is different, and has a com-plicated pathological mechanism. In this review, we discuss the pathogenesis of diabetic nephropathy in immune disorders and the intervention mechanism, to provide guidance and advice for early intervention and treatment of diabetic nephropathy.

Exendin-4, a glucagon-like peptide-1 receptor agonist, alleviates muscular dysfunction and wasting in a streptozotocin-induced diabetic mouse model compared to metformin.

Diabetic muscular atrophy is becoming a fast-growing problem worldwide, including sarcopenia, which is associated with substantial mortality and morbidity risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been marketed and suggested to exert protective effects on not only glycemic control but also diabetic complications in diabetic patients. In this study, we investigated the therapeutic use of GLP-1RAs exendin-4, compared to antidiabetic drug metformin, for the intervention of muscular dysfunction during diabetic conditions using a streptozotocin (STZ)-induced diabetic mouse model. The results showed that both exendin-4 and metformin could effectively alleviate hyperglycemia in diabetic mice, and also counteract diabetes-induced muscle weight loss, weaker grip, and changes in muscle fiber cross-sectional area distribution. Unexpectedly, exendin-4, but not metformin, enhanced the increased kidney weight and histological change in diabetic mice. Taken together, these findings suggest that both exendin-4 and metformin could effectively improve the diabetic hyperglycemia and muscular dysfunction; but exendin-4 may aggravate the nephropathy in STZ-induced diabetic mice.

PEGylation renders carnosine resistant to hydrolysis by serum carnosinase and increases renal carnosine levels.

Carnosine's protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH2). PEGylated carnosine (PEG-car) was used to study the hydrolysis of carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to carnosine or PEG-car did not influence hydrolysis of carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t1/2) in kidney, with PEG-car showing a significantly higher t1/2 compared to L-carnosine. Hence, PEGylation of carnosine is an effective approach to prevent carnosine degradations and to achieve higher renal carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation.