Sex-specific modulation of renal epigenetic and injury markers in aging kidney.

Sex differences in renal physiology and pathophysiology are well established in rodent models and humans. While renal epigenetics play a crucial role in injury, the impact of biological sex on aging kidney epigenome is less known, as most of the studies are from male rodents. We sought to determine the influence of sex and age on kidney epigenetic and injury markers, using male and female mice at 4-month (4M; young), 12-month (12M), and 24-month (24M; aged) of age. Females exhibited a significant increase in kidney and body weight and serum creatinine and decreased serum albumin levels from ages 4M to 24M, whereas minor changes were observed in male mice. Males exhibited higher levels of circulating histone 3 (H3; damage-associated molecular pattern molecules) compared with age-matched females. Kidney injury molecule-1 levels increased in serum and renal tissues from 12M to 24M in both sexes. Overall, females had markedly high histone acetyltransferase activity than age-matched males. Aged females had substantially decreased H3 methylation at lysine 9 and 27 and histone methyltransferase activity compared to aged males. Klotho levels were significantly higher in young males than females and decreased with age in males, whereas epigenetic repressor of Klotho, H3K27me3 and its enzyme, EZH2 augmented with age in both sexes. Proinflammatory NF-κB (p65) signaling increased with age in both sexes. Taken together, our data suggest that renal aging may lie in a range between normal and diseased kidneys, but differ between female and male mice, highlighting sex-specific regulation of renal epigenome in aging.

HNRNP I promotes IRAK1 degradation to reduce podocyte apoptosis and inflammatory response alleviating renal injury in diabetic nephropathy.

Podocytes maintain renal filtration integrity when the glomerular filtration barrier (GFB) is integrated. Impairment or attrition of podocytes, leading to compromised GFB permeability, constitutes the primary etiology of proteinuria and is a hallmark pathological feature of diabetic nephropathy (DN). This study centers on Heterogeneous Nuclear Ribonucleoprotein I (HNRNP I), an RNA-binding protein, delineating its role in facilitating DN-induced renal damage by modulating podocyte health. Comparative analyses in renal biopsy specimens from DN patients and high-glucose-challenged podocyte models in vitro revealed a marked downregulation of HNRNP I expression relative to normal renal tissues and podocytes. In vitro assays demonstrated that high-glucose conditions precipitated a significant reduction in podocyte viability and an escalation in markers indicative of apoptosis. Conversely, HNRNP I overexpression was found to restore podocyte viability and attenuate apoptotic indices. IRAK1, a gene encoding a protein integral to inflammatory signaling, was shown to interact with HNRNP I, which promotes IRAK1 degradation. This interaction culminates in suppressing the PI3K/AKT/mTOR signaling pathway, thereby diminishing podocyte apoptosis and mitigating renal damage in DN. This investigation unveils the mechanistic role of HNRNP I in DN for the first time, potentially informing novel therapeutic strategies for DN renal impairment.

Association of thrombotic microangiopathy with interferon therapy for hepatitis B: a case report.

BACKGROUND: Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features include vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Thrombocytopenia is one of the common adverse effects of interferon therapy. However, a more serious but rare side effect is thrombotic microangiopathy. CASE PRESENTATION: We report the case of a 36-year-old Asian male patient with clinical manifestations of hypertension, blurred vision, acute renal failure, thrombocytopenia, and thrombotic microangiopathy. Renal biopsy showed interstitial edema with fibrosis, arteriolar thickening with vitreous changes, and epithelial podocytes segmental fusion. Immunofluorescence microscopy showed C3(+), Ig A(+) deposition in the mesangial region, which was pathologically consistent with thrombotic microangiopathy renal injury and Ig A deposition. The patient had a history of hepatitis B virus infection for more than 5 years. Lamivudine was used in the past, but the injection of long-acting interferon combined with tenofovir alafenamide fumarate was used since 2018. The comprehensive clinical investigation and laboratory examination diagnosed the condition as thrombotic microangiopathy kidney injury caused by interferon. After stopping interferon in his treatment, the patient's renal function partially recovered after three consecutive therapeutic plasma exchange treatments and follow-up treatment without immunosuppressant. The renal function of the patient remained stable. CONCLUSIONS: This report indicates that interferon can induce thrombotic microangiopathy with acute renal injury, which can progress to chronic renal insufficiency.

The application of shear wave quantitative ultrasound elastography in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a major public health problem, so it is particularly important to quantitatively assess and intervene in the degree of early renal damage in CKD. OBJECTIVE: The objective of the research is to establish reference values for kidney elasticity by using real-time shear wave elastography (RT-SWE) technology to quantify Young's modulus values in the renal cortex of normal adults. The intention is to provide a foundation for evaluating renal function and structural changes in patients with CKD. Furthermore, this research investigates the role of RT-SWE in the early detection of renal fibrosis in CKD, providing insights into its diagnostic value for detecting pathological changes at an early stage. METHODS: Between August 2019 and December 2021, we collected a sample of 100 healthy people (55 men with an average age of 43.5 ± 15.2 years and 45 women with an average age of 41.6 ± 19.8 years) for medical evaluations at our hospital's Department of Ultrasound Medicine. In addition, 97 individuals with CKD1-3 stage were considered. Following the removal of contraindications and relevant confounding variables, we included a final cohort of 80 individuals in the research (45 men and 35 females, with an average age of 39.1 ± 19.2 years). The RENAL mode was selected and a convex array probe S6-1 operating at a frequency of 3.5-5.5 MHz was used in the research, which made use of the French Supersonic AixPlorer ultrasonic diagnostic instrument. Renal RT-SWE elastography was performed after conventional two-dimensional and color Doppler ultrasonography. The study used RT-SWE technology to assess the mean Young's modulus of the cortex in healthy individuals (Emean), with data analysis and comparisons based on age and gender. Furthermore, the Emean values of CKD stage 1-3 patients were determined, and analyses were performed about 24-hour urine protein quantitative (24hUTP), serum creatinine concentration (SCr), and renal biopsy pathology, specifically the degree of interstitial fibrosis. RESULTS: Healthy group: a) The average kPa values of the left kidney (4.2 ± 2.3), right kidney (4.3 + 2.5) kPa, both kidneys' average kPa values (4.3 ± 2.4) kPa, and the average kPa values of the left and right kidneys do not differ statistically (p= 0.986). b) There was no difference in the kPa values of healthy male and female kidneys (4.4 + 2.1 and 4.2 + 2.6, respectively. c) There was no difference in the renal kPa values of healthy adults aged 50 (4.4 ± 2.8) kPa and renal kPa of the 50-year-old population (4.2 + 2.1) kPa (p= 0.041). Case group: a) the group of patients with CKD1-3 stage and the group did not vary in their Emean values (both p< 0.05); b) There is a difference between CKD stages 1, 2, and 3 (p< 0.05), however, there is still no difference in the pyEmean value corrected for patient age between patients in stages 1 and 2 (p> 0.05). CONCLUSION: The study reveals no significant differences in the Emean value of bilateral kidneys in normal people and no differences in the elasticity value of kidneys and gender. However, age-based differences were statistically significant. pyEmean may be useful for comparing CKD stage 1, 2, and 3 patients, and RT-SWE can assess early renal damage.

Acute Kidney Injury in Neonatal Intensive Care Unit: Epidemiology, Diagnosis and Risk Factors.

Acute kidney injury (AKI) is associated with long-term consequences and poor outcomes in the neonatal intensive care unit. Its precocious diagnosis represents one of the hardest challenges in clinical practice due to the lack of sensitive and specific biomarkers. Currently, neonatal AKI is defined with urinary markers and serum creatinine (sCr), with limitations in early detection and individual treatment. Biomarkers and risk factor scores were studied to predict neonatal AKI, to early identify the stage of injury and not the damage and to anticipate late increases in sCr levels, which occurred when the renal function already began to decline. Sepsis is the leading cause of AKI, and sepsis-related AKI is one of the main causes of high mortality. Moreover, preterm neonates, as well as patients with post-neonatal asphyxia or after cardiac surgery, are at a high risk for AKI. Critical patients are frequently exposed to nephrotoxic medications, representing a potentially preventable cause of AKI. This review highlights the definition of neonatal AKI, its diagnosis and new biomarkers available in clinical practice and in the near future. We analyze the risk factors involving patients with AKI, their outcomes and the risk for the transition from acute damage to chronic kidney disease.

Gut microbiota dysbiosis in hyperuricaemia promotes renal injury through the activation of NLRP3 inflammasome.

BACKGROUND: The prevalence of hyperuricaemia (HUA), a metabolic disorder characterized by elevated levels of uric acid, is on the rise and is frequently associated with renal injury. Gut microbiota and gut-derived uremic toxins are critical mediators in the gut-kidney axis that can cause damage to kidney function. Gut dysbiosis has been implicated in various kidney diseases. However, the role and underlying mechanism of the gut microbiota in HUA-induced renal injury remain unknown. RESULTS: A HUA rat model was first established by knocking out the uricase (UOX). HUA rats exhibited apparent renal dysfunction, renal tubular injury, fibrosis, NLRP3 inflammasome activation, and impaired intestinal barrier functions. Analysis of 16S rRNA sequencing and functional prediction data revealed an abnormal gut microbiota profile and activation of pathways associated with uremic toxin production. A metabolomic analysis showed evident accumulation of gut-derived uremic toxins in the kidneys of HUA rats. Furthermore, faecal microbiota transplantation (FMT) was performed to confirm the effects of HUA-induced gut dysbiosis on renal injury. Mice recolonized with HUA microbiota exhibited severe renal injury and impaired intestinal barrier functions following renal ischemia/reperfusion (I/R) surgery. Notably, in NLRP3-knockout (NLRP3-/-) I/R mice, the deleterious effects of the HUA microbiota on renal injury and the intestinal barrier were eliminated. CONCLUSION: Our results demonstrate that HUA-induced gut dysbiosis contributes to the development of renal injury, possibly by promoting the production of gut-derived uremic toxins and subsequently activating the NLRP3 inflammasome. Our data suggest a potential therapeutic strategy for the treatment of renal diseases by targeting the gut microbiota and the NLRP3 inflammasome. Video Abstract.

Protective role of alpha-lipoic acid against rhabdomyolysis-induced acute kidney injury in rats.

Objectives: Rhabdomyolysis, a potentially life-threatening condition, occurs when myoglobin is released from damaged muscle cells, leading to acute kidney injury (AKI). Alpha lipoic acid (ALA), an organosulfur compound known for its anti-oxidant and anti-inflammatory properties, was examined in this study for its potential impact on rhabdomyolysis-induced AKI in rats. Materials and Methods: Six groups of rats were included in the study, with each group consisting of six rats (n=6): Control, rhabdomyolysis, rhabdomyolysis treated with different doses of ALA (5, 10, and 20 mg/kg), and ALA alone (20 mg/kg) groups. Rhabdomyolysis was induced by intramuscular injection of glycerol on the first day of the experiment, while ALA was administered intraperitoneally for four consecutive days. Renal function parameters, oxidative stress markers, and histological changes in the kidneys were evaluated. Western blot analysis was performed to measure the levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) proteins. Results: A significant increase in serum urea, creatinine, renal malondialdehyde, NGAl, and TNF-α protein levels was observed in glycerol-injected rats. In addition, a significant decrease in glutathione was recorded. Compared to the rhabdomyolysis group, treatment with ALA recovered kidney histological and biochemical abnormalities. Conclusion: Results suggest that rhabdomyolysis-induced AKI is associated with increased oxidative stress and inflammation. Treatment with ALA improved kidney histological abnormalities and reduced oxidative stress markers in rats. Therefore, ALA may have a potential protective effect against rhabdomyolysis-induced AKI.

Effect of access sheath diameter used in percutaneous nephrolithotomy on renal function: a prospective randomized study.

We aimed to determine the effect of the access sheath diameter used in percutaneous nephrolithotomy (PNL) on renal function. We also investigated the predictors of impaired renal function. Data were prospectively collected from patients who underwent PNL from December 2020 to December 2021. The patients were randomized into two groups according to access sheath diameter: Group 1 (22 Fr, n = 44) and Group 2 (28 Fr, n = 44). Relative renal function (RRF) was calculated by technetium-99 m dimercaptosuccinic acid scintigraphy, and glomerular filtration rate (GFR) was calculated by diethylenetriamine pentaacetic acid scintigraphy. A difference of 5% or more in RRF was considered a significant functional change. Preoperative and postoperative Kidney Injury Molecule-1 (KIM-1) levels were measured. Preoperative demographic data and stone characteristics were similar between the groups. There were also no statistically significant differences between the groups in terms of scar development, changes in RRF, GFR, or KIM-1/creatinine (Cr) (p > 0.05). Significant deterioration in RRF was detected in a total of six (6.8%) patients, three in each group. The factors predicting loss of function were analyzed by regrouping the patients without loss of function as Group A (n = 82) and those with loss as Group B (n = 6). Only stone volume was statistically significant in multivariate analysis (p = 0.002). Access sheath diameter had no significant effect on renal function after PNL. However, the stone volume was found to independently correlate to a loss of renal function after PNL.

SB-525334 ameliorates renal injury in diabetic kidney disease mouse model via suppressing inflammation.

BACKGROUND: Diabetic kidney disease (DKD; also known as diabetic nephropathy) is a typical complication of diabetes mellitus characterised by renal injury due to disturbances in glucose metabolism, in which renal tubular damage caused by chronic inflammation has been shown to be closely associated with the development of end-stage renal disease (ESRD). However, there are insufficient effective therapeutic agents to halt the progression of DKD. METHODS: In the present study, we screened differential gene expression profiles associated with DKD by mining the GEO database through differential and enrichment analyses. Furthermore, systemic in vivo and in vitro experiments were designed to explore the mechanism through which the potential therapeutic agent SB-525334 improves DKD. RESULTS: SB-525334 ameliorated DKD-induced kidney injury by regulating inflammatory cytokines (TGF-ß1, IL-6, IL-10) as well as promoting the translation of M1 (iNOS) macrophage to M2 (CD206) macrophage. In addition, SB-525334 ameliorates kidney injury caused by DKD through inhibiting inflammation through regulating the expression of key proteins in the TGF-ß1 /JNK and TGF-ß1 /Smad signaling pathways. For studies in vitro, inflammation induced by LPS in vitro was inhibited significantly after the administration of SB-525334 through down-regulating pro-inflammatory cytokines, promoting macrophage conversion from M1 to M2, and inhibiting the activation of TGF-ß1 /JNK and TGF-ß1 /Smad pathways. CONCLUSIONS: These results highlight that the target compound SB-525334 could serve as a novel potential therapeutic agent and ameliorate DKD in an inflammation-inhibiting manner.

Simiao pills alleviates renal injury associated with hyperuricemia: A multi-omics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Simiao Pills, a classical traditional Chinese medicine prescription recorded in Cheng Fang Bian Du, has been traditionally used to treat hyperuricemia due to its heat-clearing and diuretic properties. Studies have shown that Simiao Pills effectively reduce uric acid levels. However, further research is needed to elucidate the precise composition of Simiao Pills for treating hyperuricemia and their potential pharmacological mechanism. AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of Simiao Pills on hyperuricemia, with a particular focus on evaluating their protective role against hyperuricemia-induced renal injury and elucidating the underlying mechanism of action. MATERIALS AND METHODS: UPLC-MS/MS was used to identify the components of Simiao Pills. The hyperuricemia model mice were established by intraperitoneal injecting potassium oxonate (PO) and oral administrating hypoxanthine (HX). Network pharmacology, transcriptome, and metabolomics analyses were integrated to explore the mechanism of Simiao Pills in reducing uric acid and protecting the kidney. Mechanistic and functional studies were conducted to validate the potential mechanisms. RESULTS: Simiao Pills were found to contain 12 characteristic components. Treatment with Simiao Pills significantly reduced serum uric acid levels and ameliorated hyperuricemia-induced renal injury. Simiao Pills inhibited the enzymatic activities of XOD and XDH, and regulated the uric acid transporters in the kidney and ileum. Transcriptome and network pharmacology analyses highlighted quercetin, berberine, kaempferol, and baicalein as the principal active components of Simiao Pills acting on the kidney during hyperuricemia treatment, primarily impacting fibrosis, apoptosis, and inflammation-related signaling pathways. Metabolomic analysis unveiled 21 differential metabolites and 5 metabolic pathways associated with Simiao Pills against renal injury associated with hyperuricemia. Further experimental results validated that Simiao Pills reduced renal fibrosis, apoptotic renal cells, serum inflammation levels, and inhibited the NF-κB/NLRP3/IL-1ß signaling pathway. CONCLUSION: This study demonstrated that Simiao Pills significantly reduced serum uric acid levels and improved renal injury by regulating inflammation, apoptosis, and renal fibrosis. These findings have provided a robust scientific pharmacological basis for the use of Simiao Pills in treating hyperuricemia patients.

Exploring the Role of Phenolic Compounds in Chronic Kidney Disease: A Systematic Review.

Chronic kidney disease (CKD) presents a formidable global health concern, affecting one in six adults over 25. This review explores the potential of phenolic compounds in managing CKD and its complications. By examining the existing research, we highlight their diverse biological activities and potential to combat CKD-related issues. We analyze the nutritional benefits, bioavailability, and safety profile of these compounds. While the clinical evidence is promising, preclinical studies offer valuable insights into underlying mechanisms, optimal dosages, and potential side effects. Further research is crucial to validate the therapeutic efficacy of phenolic compounds for CKD. We advocate for continued exploration of their innovative applications in food, pharmaceuticals, and nutraceuticals. This review aims to catalyze the scientific community's efforts to leverage phenolic compounds against CKD-related challenges.

The Development of IgE Multiple Myeloma Following Treatment for Locally Advanced Prostate Cancer.

This case report documents the diagnosis of multiple myeloma (MM) in a 74-year-old man following treatment for locally advanced prostate cancer. It is important to include MM in the differential diagnosis when the patient presents with nonspecific symptoms such as back pain, anemia, and renal impairment in the absence of a prominent increase in prostate-specific antigen (PSA). The present case was diagnosed as IgE MM with a poor prognosis. Prompt diagnosis and intervention of MM is necessary to avoid complications, including renal impairment.

Aqueous extract of Phellinus igniarius ameliorates hyperuricemia and renal injury in adenine/potassium oxonate-treated mice.

Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.

The renoprotective potential of montelukast: a scoping review.

Introduction: Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney function, while chronic kidney disease involves a gradual deterioration lasting more than 3 months. Mechanisms of renal injury include impaired microcirculation, inflammation, and oxidative stress. Cysteinyl-leukotrienes (CysLTs) are inflammatory substances contributing to tissue damage. Montelukast, a leukotriene receptor antagonist, has shown potential renoprotective effects in experimental models of kidney injury. Methods: The authors conducted a scoping review using PubMed, Scopus, and Web of Science databases to identify relevant studies investigating the impact of montelukast on renal diseases. Articles published until 2022 were included and evaluated for quality. Data extraction and analysis were performed based on predetermined inclusion criteria. Results: The scoping review included 30 studies from 8 countries. Montelukast demonstrated therapeutic effects in various experimental models of nephrotoxicity and AKI induced by agents such as cisplatin, lipopolysaccharide, diclofenac, amikacin, Escherichia coli, cyclosporine, methotrexate, cobalt-60 gamma radiation, doxorubicin, and cadmium. Studies involving human subjects with nephrotic syndrome, pyelonephritis, and other renal diseases also reported positive outcomes with montelukast treatment. Montelukast exhibited anti-inflammatory, anti-apoptotic, antioxidant, and neutrophil-inhibiting properties, leading to improved kidney function and histopathological changes. Conclusions: Montelukast shows promise as a renoprotective medication, particularly in early-stage kidney injury. Its ability to mitigate inflammation, oxidative stress, and neutrophil infiltration contributes to its therapeutic effects. Further research is needed to explore the clinical applications and mechanisms underlying the renoprotective action of montelukast.

Targeted Drug Therapy for Senescent Cells Alleviates Unilateral Ureteral Obstruction-Induced Renal Injury in Rats.

Hydronephrosis resulting from unilateral ureteral obstruction (UUO) is a common cause of renal injury, often progressing to late-stage renal fibrosis or even potential renal failure. Renal injury and repair processes are accompanied by changes in cellular senescence phenotypes. However, the mechanism is poorly understood. The purpose of this study is to clarify the changes in senescence phenotype at different time points in renal disease caused by UUO and to further investigate whether eliminating senescent cells using the anti-senescence drug ABT263 could attenuate UUO-induced renal disease. Specifically, renal tissues were collected from established UUO rat models on days 1, 2, 7, and 14. The extent of renal tissue injury and fibrosis in rats was assessed using histological examination, serum creatinine, and blood urea nitrogen levels. The apoptotic and proliferative capacities of renal tissues and phenotypic changes in cellular senescence were evaluated. After the intervention of the anti-senescence drug ABT263, the cellular senescence as well as tissue damage changes were re-assessed. We found that before the drug intervention, the UUO rats showed significantly declined renal function, accompanied by renal tubular injury, increased inflammatory response, and oxidative stress, alongside aggravated cellular senescence. Meanwhile, after the treatment with ABT263, the rats had a significantly lower number of senescent cells, attenuated renal tubular injury and apoptosis, enhanced proliferation, reduced oxidative stress and inflammation, improved renal function, and markedly inhibited fibrosis. This suggests that the use of the anti-senescence drug ABT263 to eliminate senescent cells can effectively attenuate UUO-induced renal injury. This highlights the critical role of cellular senescence in the transformation of acute injury into chronic fibrosis.

Abnormal epigenetic memory of mesenchymal stem and progenitor cells caused by fetal malnutrition induces hypertension and renal injury in adulthood.

Fetal malnutrition has been reported to induce hypertension and renal injury in adulthood. We hypothesized that this hypertension and renal injury would be associated with abnormal epigenetic memory of stem and progenitor cells contributing to organization in offspring due to fetal malnutrition. We measured blood pressure (BP) for 60 weeks in offspring of pregnant rats fed a normal protein diet (Control), low-protein diet (LP), and LP plus taurine (LPT) in the fetal period. We used western blot analysis to evaluate the expression of αSMA and renin in CD44-positive renal mesenchymal stem cells (MSCs) during differentiation by TGF-ß1. We measured kidney label-retaining cells (LRCs) at 11 weeks of age and formation of endothelial progenitor cells (EPCs) at 60 weeks of age from the offspring with fetal malnutrition. Epigenetics of the renal MSCs at 14 weeks were investigated by ATAC-sequence and RNA-sequence analyses. BP was significantly higher in LP than that in Control and LPT after 45-60 weeks of age. Numbers of LRCs and EPC colonies were significantly lower in LP than in Control. Renal MSCs from LP already showed expression of h-caldesmon, αSMA, LXRα, and renin before their differentiation. Epigenetic analyses identified PAR2, Chac1, and Tspan6 genes in the abnormal differentiation of renal MSCs. These findings suggested that epigenetic abnormalities of stem and progenitor cell memory cause hypertension and renal injury that appear in adulthood of offspring with fetal malnutrition.

Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.

BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Ameliorative impacts of astaxanthin against atrazine-induced renal toxicity through the modulation of ionic homeostasis and Nrf2 signaling pathways in mice.

Astaxanthin (ASX), a red pigment belonging to carotenoids, has antioxidant activity and anti-oxidative stress effect. Atrazine (ATZ), a frequently used herbicide, whose degradation products are the cause for nephrosis and other oxidative stress associated diseases. This study was aimed to reveal the potential protective mechanism of astaxanthin against atrazine-induced nephrosis. Atrazine was orally given (250 mg/kg bw) to the mice along with astaxanthin (100 mg/kg bw) for 28 days. Serum biochemical indicators, oxidative stress biomarkers, ATPase activities, ion concentration, histomorphology, and various renal genes expression linked with apoptosis, Nrf2 signaling pathway, and aquaporins (AQPs) were assessed. It was found that serum creatinine (SCr), blood urea nitrogen (BUN), and MDA levels were significantly increased after the treatment of atrazine, whereas serum renal oxidative stress indicators like CAT, GSH, T-AOC, SOD decreased. Renal histopathology showed that atrazine significantly damaged renal tissues. The activities of Ca 2+-Mg 2+-ATPase were increased whereas Na +-K +-ATPase decreased significantly (P < 0.05). Moreover, results confirmed that the expression of AQPs, Nrf2, and apoptosis genes were also altered after atrazine administration. Interestingly, astaxanthin supplementation significantly (P < 0.05) improved atrazine-induced nephrotoxicity via decreasing SCr, BUN, oxidative stress, ionic homeostasis and reversing the changes in AQPs, Nrf2, and apoptosis gene expression. These findings collectively suggested that astaxanthin has strong potential ameliorative impact against atrazine induced nephrotoxicity.