Stress hyperglycemia ratio (SHR) has been associated with increased mortality from various cerebrovascular events and a higher incidence of acute kidney injury (AKI) in certain patient populations. However, the relationship between SHR and the mortality risk in patients with AKI has not been fully elucidated. Our study sought to comprehensively investigate the association and potential mediating effects between SHR and 28-day and 90-day mortality in patients with AKI.

3703 patients with AKI were included in this study. Feature importance variables were screened by a random forest algorithm, and the independent association of SHR with mortality risk was determined by Kaplan ‒ Meier survival analysis with Cox regression analysis. Restricted cubic spline (RCS) was conducted to assess the non-linear relationship between SHR and mortality risk. Mediation analysis was deployed to investigate the indirect effect of SHR on respiratory failure (RF) -mediated mortality risk.

Among the patients with AKI included in this study, the 28-day mortality was 13.6% and the 90-day mortality was 18.7%. Fully adjusted Cox regression demonstrated that SHR was an independent risk factor for 28-day mortality (HR, 1.77 [95% CI 1.38-2.27], P < 0.001) and 90-day mortality (HR, 1.69 [95% CI 1.36-2.11], P < 0.001) in patients with AKI. RCS analysis revealed a linear relationship between SHR and outcome events. Additionally, the effect of SHR on 28-day and 90-day mortality risk were mediated by an increased RF risk in 6.62% and 6.54%, respectively.

High SHR is an independent risk factor for 28-day and 90-day mortality in patients with AKI, and its effect is partly mediated by an increased risk of RF.

Diabetic kidney disease (DKD) is a common complication in patients with diabetes, and glycolipid metabolism disorders are an important cause of DKD. The root of Oxybaphus himalaicus (Edgew.) Heimerl is a traditional Tibetan medicine commonly used to treat kidney-related diseases. Nevertheless, contemporary pharmacological investigations into O. himalaicus, especially those associated with the treatment of renal disorders, remain scarce. The objective of this research was to explore the pharmaceutical impacts and mechanisms of action of O. himalaicus in the treatment of DKD. The active fraction and potential pharmacological effects of O. himalaicus were determined through network pharmacology. Then, in vivo and in vitro efficacy and mechanism studies were conducted through streptozotocin-induced DKD mice and high glucose-induced HK-2 cells. Network pharmacology research speculated the ethyl acetate (EA) fraction as the main active component of O. himalaicus for treating DKD. In vivo and in vitro experiments showed that EA reduces renal lipotoxicity by upregulating PPARα pathway proteins, enhancing fatty acid oxidation (FAO), and downregulating inflammatory factors such as TNF-α and IL-6. Molecular docking studies revealed that the active components of EA with a high affinity for PPARα are mainly rotenoid compounds. EA mitigates DKD through the activation of PPARα, which serves to augment FAO, abate lipid accumulation, and impede the expression of inflammatory factors. Among these, rotenoids may be the main active components that exert pharmacological effects.

The occurrence of diabetic kidney disease (DKD), a critical microvascular issue in diabetes, is progressively on the rise. In recent years, long noncoding RNAs (lncRNAs) have garnered considerable attention as a novel and critical layer of biological regulation. Our knowledge regarding the roles and underlying mechanisms of lncRNAs in various diseases, including DKD, continues to evolve. Similarly, microRNAs (miRNAs), which are small noncoding RNAs, have been recognized as crucial contributors to cellular processes and disease pathogenesis. Emerging studies have highlighted the complex interactions between lncRNAs and miRNAs, particularly in the context of DKD, underscoring their importance in complex human diseases. Renal intrinsic cell damage is an important cause of inducing DKD. Persistent high glucose stimulation leads to remodeling of renal intrinsic cells and a cascade of pathological changes. This article aims to review recent literature on the lncRNAs-mediated regulation of miRNAs affecting renal intrinsic cells in DKD and to propose novel molecular-level therapeutic strategies for DKD. Through in-depth investigation of this dynamic molecular interaction, we can gain a profound understanding of the potential mechanisms underlying diabetic nephropathy, potentially identifying new targets for therapeutic intervention and paving the way for personalized and effective treatments.

N6-methyladenosine (m6A), a prevalent and essential RNA modification, serves a key function in driving autoimmune disease pathogenesis. By modulating immune cell development, activation, migration, and polarization, as well as inflammatory pathways, m6A is crucial in forming innate defenses and adaptive immunity. This article provides a comprehensive overview of m6A modification features and reveals how its dysregulation affects the intensity and persistence of immune responses, disrupts immune tolerance, exacerbates tissue damage, and promotes the development of autoimmunity. Specific examples include its contributions to systemic autoimmune disorders like lupus and rheumatoid arthritis, as well as conditions that targeting specific organs like multiple sclerosis and type 1 diabetes. Furthermore, this review explores the therapeutic promise of target m6A-related enzymes ("writers," "erasers," and "readers") and summarizes recent advances in intervention strategies. By focusing on the mechanistic and therapeutic implications of m6A modification, this review sheds light on its role as a promising tool for both diagnosis and treatment in autoimmune disorders, laying the foundation for advancements in customized medicine.

Virtually all cell types are capable of secreting small extracellular vesicles (sEV), which can be internalized by recipient cells, thereby serving as vehicles for intercellular communication. The cargoes of these vesicles, such as microRNAs, circular RNAs, proteins, and lipids, play significant roles in both normal cellular functions and the pathogenesis of various diseases. Diabetic Nephropathy (DN), a complication arising from diabetes, is expected to contribute to a 54% increase in the global diabetic population between 2015 and 2030, leading to substantial economic burdens on individuals and healthcare systems. sEVs, as promising biomarkers, demonstrate diverse mechanistic responses in different types of Diabetic Kidney Disease (DKD). They also hold advantages in the early prediction of renal damage. This article reviews the functional mechanisms of sEVs in DKD and their potential as therapeutic targets and biomarkers.

Diabetic kidney disease (DKD) is one of the complications of diabetes mellitus, which triggers kidney fibrosis and eventually develops into end-stage renal disease. Nuciferine (NF) is one of the most important functional components in lotus leaves (LL), but its role and mechanism for the treatment of DKD are unclear. A high-fat-diet (HFD)-induced DKD model in KK-AY mice was established in this study. NF treatment significantly improved blood glucose and blood biochemical indices in DKD mice. Furthermore, NF reduced the levels of mALB, UCRE, Scr, and BUN in mice urine. Further, the extent of renal lesions in the mice in this study was at stage IV according to the Mogensen staging method. NF treatment was effective in ameliorating renal injury during this period. Concurrently, the protein levels of FN, N-cadherin, TGFβ, p-Smad3, p-PI3K, p-AKT, p-mTOR, and p62 were decreased. In contrast, the level of expression of Beclin-1 was increased. In the high glucose-exposed HK-2 cell model, the expression of p-PI3K, p-AKT, and p-mTOR was all downregulated, and autophagy proteins were increased after NF intervention. In addition, HK-2 cells were treated with high glucose in combination with Wortmannin and 3-MA, respectively. The results demonstrated that NF inhibited the expression of TGFβ and p-Smad3 by regulating autophagy through the PI3K-AKT-mTOR pathway, thereby ameliorating renal fibrosis at stage IV in mice. Therefore, LL can be used as a dietary component for the prevention of renal fibrosis in DKD patients.

Epimedium glycoside is a flavonoid compound in Epimedium, which has been found to alleviate various chronic diseases. The effect and mechanism of icariin on the treatment of diabetes nephropathy still need to be clarified. In this study, we conducted network pharmacology and molecular docking analysis to reveal the mechanism of icariin treating DKD, and then validated its efficacy using a cell model.

The structure and targets of icariin were screened using Traditional Chinese Medicine Systems Pharmacology (TCMSP), and their targets were annotated. Retrieve DKD targets from OMIM, GeneCards, and TTD databases. We constructed a protein-protein interaction (PPI) network using the STRING platform and visualized the results using Cytoscape 3.9.1 software. We also conducted GO and KEGG enrichment analysis on icariin and then performed molecular docking between icariin and key targets. Finally, we established a cell model of DKD to evaluate the efficacy of icariin in treating DKD.

A total of 77 icariin targets were associated with DKD. The GO and KEGG enrichment results showed that the therapeutic effect of icariin on DKD was significantly correlated with inflammatory response, cell apoptosis, epithelial-mesenchymal transition, and PI3K/AKT signaling pathway. The molecular docking results indicate that icariin has a high affinity for key targets EGER, AKT1, and IGF1. Cell experiments showed that icariin inhibited high glucose-induced EMT, fibrosis-related proteins, levels of inflammatory factors TGF-β1, IL-6, and TNF-α, as well as phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in renal tubular epithelial cells. In addition, icariin inhibited the increase in EGER and AKT1 mRNA levels caused by high glucose and alleviated the decrease in IGF1 mRNA levels.

Epimedium glycoside may protect DKD by targeting EGER, AKT1, and IGF1 to inhibit PI3K/AKT signaling, but the specific mechanism needs further exploration.

Diabetic nephropathy (DN) represents the primary cause of chronic kidney disease (CKD) worldwide. Orientin is a natural bioactive flavonoid with profound immunomodulatory, anti-inflammatory, and antioxidative effects. This study aimed to investigate the nephroprotective effect of orientin on rat prototypes of high-fat diet (HFD) and streptozotocin (STZ)-induced DN. 75 male rats were divided into 5 groups of 15 rats each. Rats were fed a HFD for 4 weeks, injected with a single dose of STZ 30 mg/kg, and continued on HFD for 15 weeks. Orientin was administered daily at 40 mg/kg for 15 weeks. The diabetic group reported substantially greater fasting blood glucose, HbA1c, and renal function measures than normal controls, as well as notable kidney histological abnormalities such as interstitial inflammation, glomerular shrinkage, and tubular necrosis. Additionally, the diabetic group showed dramatically greater amounts of IL-1β, IL-6, TNF-α, TGF-β1, MDA, and a much lower level of GSH than the control group. However, orientin had no effect on the glycaemic parameters, but it dramatically reduced blood creatinine levels, prevented the development of histopathological irregularities, and minimized the renal concentrations of inflammatory and oxidative markers. Orientin may be a promising natural medication for improving diabetic nephropathy thanks to its robust anti-inflammatory and anti-proliferative properties.

Diabetic nephropathy is a prevalent complication of diabetes and stands as the primary contributor to end-stage renal disease. The global prevalence of diabetic nephropathy is on the rise, however, due to its intricate pathogenesis, there is currently an absence of efficacious treatments to enhance renal prognosis in affected patients. The mammalian target of rapamycin (mTOR), a serine/threonine protease, assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress. In this academic review, we have consolidated the understanding of the pathological mechanisms associated with four distinct resident renal cell types (podocytes, glomerular mesangial cells, renal tubular epithelial cells, and glomerular endothelial cells), as well as macrophages and T lymphocytes, within a diabetic environment. Additionally, we highlight the research progress in the treatment of diabetic nephropathy with drugs and various molecules interfering with the mTOR signaling pathway, providing a theoretical reference for the treatment and prevention of diabetic nephropathy.

Diabetic kidney disease is a major microvascular diabetes mellitus (DM) complication clinically associated with a gradual renal function decline. Although metformin is a common drug for managing DM, however, monotherapy treatment with any antidiabetic drug will necessitate dosage increment since type 2 DM (T2DM) deteriorates over time due to the increasing pancreatic β-cell dysfunction and will eventually require a combination therapy approach with another antidiabetic medication. Vitamin D is a food supplement that has been proven to have antidiabetic and reno-protective activities. Hence, we explore the combination of vitamin D and metformin on T2DM-induced renal dysfunction. Thirty male Wistar rats were randomized into five (5) groups: control, diabetes untreated, diabetics treated with metformin, vitamin D, and vitamin D + metformin. Vitamin D and metformin significantly reversed DM-induced hyperglycemia, electrolyte imbalance, and dyslipidemia. Also, vitamin D and metformin reversed T2DM-induced increase in serum creatinine and urea and renal lactate, LDH, and oxido-inflammatory response. These observed alterations were accompanied by an increase in proton pump activities and modulation of Nrf2/Nf-κB and XO/UA signaling. This study revealed that vitamin D and/or metformin ameliorated T2DM-induced renal injury.

In this study, we designed and synthesized a novel thio-purine analog, compound 1, which exhibits significant fluorescence properties due to its extended conjugated system, heteroatom incorporation (O, S, N), and rigid three-dimensional molecular framework, enabling its use as a fluorescence probe for real-time drug tracking and release monitoring. To enhance the solubility, biocompatibility, and therapeutic efficacy of compound 1, we synthesized a copper(II)-based coordination polymer (CP1) via hydrothermal methods, featuring a three-dimensional framework formed by 1,4-ttb and auxiliary ligand 4,4'-bpdc, as confirmed by comprehensive characterization techniques. Leveraging the synergistic therapeutic effects of compound 1 and fenelidone, we developed a composite drug delivery system, mPEG-PSU@CP1@1@fenelidone, which combines an amphiphilic mPEG-PSU shell with a CP1 core co-encapsulating both drugs. Notably, the fluorescence properties of compound 1 allow for real-time monitoring of drug release, as its fluorescence is quenched when encapsulated in CP1 and restored upon release. This system optimizes controlled drug release while enhancing the synergistic effects of compound 1 and fenelidone in reducing inflammation and renal fibrosis, as demonstrated in diabetic nephropathy (DN) model mice. Overall, the composite system integrates real-time fluorescence monitoring with improved therapeutic efficacy, offering a promising strategy for diabetic nephropathy treatment.

Diabetes mellitus (DM) and its various complications, including diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and ulcers, pose significant challenges to global health. This review investigates the potential of procyanidins (PCs), a natural polyphenolic compound, in preventing and managing diabetes and its complications. PCs, recognized for their strong antioxidant, anti-inflammatory, and anti-hyperglycemic properties, play a crucial role in reducing oxidative stress and enhancing endothelial function, which are essential for managing diabetic complications. This review elucidates the molecular mechanisms by which PCs improve insulin sensitivity and endothelial health, thereby providing protection against the various complications of diabetes. The comprehensive analysis underscores the promising therapeutic role of PCs in diabetes care, indicating the need for further clinical studies to confirm and leverage their potential in comprehensive diabetes management strategies.

Background: Excessive accumulation of glomerular extracellular matrix (ECM) is a key factor in the development and progression of diabetic nephropathy (DN). As kidney dysfunction has been reported in normoalbuminuric patients, identifying novel diagnostic and prognostic markers is essential for the prevention and treatment of DN. Methods: Urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) and ECM-related glycoproteins, i.e., fibronectin (FN) and laminin (LN), was measured in obese patients with newly diagnosed type 2 diabetes mellitus (T2DM) before and after 6 months of metformin therapy. Results: Baseline NGAL (1.27 (0.80-2.36) ng/mg Cr), FN (11.19 (5.31-21.56) ng/mg Cr) and LN (123.17 (54.56-419.28) pg/mg Cr) levels did not significantly differ between T2DM patients and controls (1.95 (1.09-2.97) ng/mg Cr, 11.94 (7.78-18.01) ng/mg Cr and 157.85 (83.75-326.40) pg/mg Cr, respectively). In multivariate regression analysis, the body mass index was identified as the only significant predictor influencing urinary NGAL and FN levels at baseline, with β = 0.249, p = 0.005 and β = 1.068, p = 0.010, respectively. Metformin treatment significantly increased urinary levels of both ECM proteins, i.e., FN (18.48 (11.64-32.46) ng/mg Cr) and LN (179.51 (106.22-414.68) pg/mg Cr), without any effect on NGAL levels (1.44 (0.81-2.72) ng/mg Cr). FN and LN were positively associated with NGAL both before (r = 0.709 and r = 0.646, both p < 0.001, respectively) and after (r = 0.594 and r = 0.479, both p < 0.001, respectively) therapy. No correlations were found between NGAL, FN, LN, and albuminuria. However, NGAL was positively correlated with the albumin/creatinine ratio (ACR) both before (r = 0.323, p < 0.05) and after (r = 0.287, p < 0.05) therapy, and negatively with estimated glomerular filtration rate (eGFR) in pre-treatment diabetics (r = -0.290, p < 0.05). FN and LN were also correlated with ACR (r = 0.384, p < 0.01 and r = 0.470, p < 0.001), although the association for LN was limited to untreated patients (r = 0.422, p < 0.01). Conclusions: Our results suggest that metformin has a beneficial effect on ECM turnover with a significant increase in urinary excretion of non-collagenous markers of glomerular injury, i.e., FN and LN. Additionally, ECM-related markers may serve as useful tools for monitoring early renal injury in obese diabetic patients.

N5-methylcytosine (m5C) methylation is involved in various disease progression; however, its role in diabetic nephropathy (DN) has not been studied. The aim of this study was to investigate the role of NSUN2 in DN and the underlying mechanism.

Streptozotocin-induced experimental mouse model was generated to analyze the role of NSUN2 in vivo, and high glucose (HG)-treated Raw264.7 cells were used to assess the effect of NSUN2 on macrophage infiltration in vitro. The regulation of NSUN2 on SOCS1 m5C methylation was evaluated using m5C methylated RNA immunoprecipitation, luciferase reporter analysis, and RNA stability determination assay.

The results indicated that NSUN2 was highly expressed in the blood and kidney of DN mice. Knockdown of NSUN2 alleviated kidney damage, reduced blood glucose and urine albumin, and suppressed macrophage infiltration in DN mice. Moreover, NSUN2 interacted with SOCS1, and silenced NSUN2 inhibited m5C levels of SOCS1 to reduce SOCS1 mRNA stability. Additionally, interference with NSUN2 suppressed macrophage migration, invasion, and infiltration by positively regulating SOCS1 expression under HG conditions.

In conclusion, silencing of NSUN2 inhibits macrophage infiltration by reducing m5C modification of SOCS1, and thereby attenuates renal injury. The findings suggest a novel regulatory mechanism between NSUN2-mediated m5C modification and DN.

Diabetic kidney disease is a significant complication of diabetes mellitus, and exposure to certain chemicals may play a role in its development. Triphenyl phosphate (TPHP) is commonly used in plastics and flame retardants. This study aims to investigate the potential impact of TPHP and its metabolite diphenyl phosphate (DPHP) on diabetic kidney disease using various methods, including network toxicology, molecular docking, and cell experiments like CCK8 assay and real-time-PCR. The research examined the relationship between urinary DPHP levels and kidney function in American adults using data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to March 2020. Additionally, the study explored the targets of action for TPHP and DPHP using network toxicity analysis, conducted protein interaction analysis, and explored the functional aspects of action through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Furthermore, the study identified key proteins involved in the action and conducted experimental verification by treating cells with TPHP and DPHP. Toxicity analysis showed that TPHP could cause dose-dependent toxicity in mouse podocyte clone 5 (MPC5) and mouse mesangial cells (MES13). The study also detected mRNA expression of core targets molecularly docked with TPHP and DPHP using real-time-PCR. The results indicated statistically significant regulation of most core targets by TPHP and DPHP in MPC5, MES13, and human kidney-2 cells.

Mizagliflozin (MIZ) is a specific inhibitor of sodium-glucose cotransport protein 1 (SGLT1) originally developed as a medication for diabetes.

To explore the impact of MIZ on diabetic nephropathy (DN).

Diabetic mice were created using db/db mice. They were administered either a low dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks. Subsequently, mesangial cells (MCs) were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN.

The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice. High doses of MIZ led to a substantial increase in body weight in mice, along with decreased blood glucose levels and food intake. Moreover, the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes, such as collagen type 1 alpha 1 mRNA levels. While the expression of SGLT1 increased after exposure to high glucose, it decreased following treatment with MIZ. Furthermore, MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin. MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione, while reducing malondialdehyde levels.

These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1, inflammation, and oxidative stress.

Previous research has shown a strong association between insulin resistance (IR) and both the onset and advancement of diabetic kidney disease (DKD). This research focuses on examining the relationship between IR and all-cause mortality in individuals with DKD.

This study utilized data obtained from the National Health and Nutrition Examination Survey (NHANES), spanning the years 2001 to 2018. Insulin resistance was assessed using reliable indicators (HOMA-IR, TyG, TyG-BMI, and METS-IR). The relationship between IR indices and survival outcomes was evaluated through weighted multivariate Cox regression, Kaplan-Meier survival analysis, and restricted cubic spline (RCS) modeling. To examine non-linear associations, the log-likelihood ratio test was employed, with piecewise regression models used to establish confidence intervals and identify threshold values. Diagnostic precision and efficacy were gauged using Receiver Operating Characteristic (ROC) curves, Area Under the Curve (AUC) evaluations, and calibration plots. Moreover, to verify the consistency of our results, stratified analyses and interaction tests were conducted across variables including age, gender, Body Mass Index (BMI), hypertension, and cardiovascular status.

This research involved a group of 1,588 individuals diagnosed with DKD. Over a median observation period of 74 months, 630 participants passed away. Using weighted multivariate Cox regression along with restricted cubic spline modeling, we identified non-linear associations between the four insulin resistance indices and all-cause mortality. An analysis of threshold effects pinpointed essential turning points for each IR index in this research: 1.14 for HOMA-IR, 9.18 for TyG, 207.9 for TyG-BMI, and 35.85 for METS-IR. It was noted that levels below these thresholds inversely correlated with all-cause mortality. In contrast, values above these points showed a significantly positive correlation, suggesting heightened mortality risks. The accuracy of these four IR metrics as indicators of all-cause mortality was confirmed through ROC and calibration curve analyses.

In patients with DKD, an L-shaped association is noted between HOMA-IR and all-cause mortality, while TyG, TyG-BMI, and METS-IR exhibit U-shaped relationships. All four IR indices show good predictive performance.

The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX is a copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of LOX in partial EMT and fibrotic progression in diabetic nephropathy has not been investigated experimentally.

The bulk RNA sequencing and single-nuclei RNA sequencing (snRNA-seq) analysis were explored to find the role of LOX in diabetic nephropathy. We then investigated the partial EMT and the possible signaling pathway of LOX, both in vivo and in vitro by LOX inhibition experiments in diabetic mice and HK-2 cells. Besides, we further assessed kidney fibrosis and renal function.

LOX expression was elevated in kidneys of diabetic mice. Additionally, snRNA-seq results indicated that LOX expression was higher in partial epithelial-mesenchymal transition proximal tubular (PemtPT) epithelial cells. Moreover, we found that increased LOX prompted partial EMT of renal tubular epithelial cells (RTECs) by modulating the transcription factor Snail both in vivo and in vitro. Remarkably, inhibition of LOX effectively mitigated the partial EMT of RTECs in diabetic mice, thereby attenuating kidney fibrosis and enhancing renal function. Additionally, we identified the TGF-β signaling pathway as an upstream regulator of LOX, and inhibiting LOX partially reversed the partial EMT program in HK-2 cells induced by the TGF-β signaling pathway.

Hyperglycemia induces partial EMT of RTECs via the TGF-β/LOX/Snail axis, thereby contributing to diabetic kidney fibrosis. Inhibiting LOX can effectively reverse the partial EMT of RTECs, diminish diabetic kidney fibrosis, and improve renal function.

Diabetic nephropathy (DN) is one of the most severe kidney complications and the primary contributor to end-stage renal disease on a global scale. It exacerbates the morbidity, mortality, and financial burden for individuals with diabetes. Isoquercitrin, a natural compound found in various plants, has demonstrated potential as an antidiabetic agent. However, it remains uncertain whether isoquercitrin exerts a protective effect on DN. Therefore, the objective of this study was to explore whether isoquercitrin confers a protective effect on DN and its potential mechanism. In vivo, a mouse model of DN induced by streptozotocin was established in the study. The hypoglycemic effect of isoquercitrin was assessed by measuring fasting blood glucose levels, insulin tolerance tests, and glucose tolerance test in animals. Urinary albumin creatinine ratio, serum lipid levels, and pathological changes in renal tissues were measured to evaluate the protective effect of isoquercitrin against DN. The expression of Sodium glucose co-transporter-2(SGLT2) was analyzed using real-time quantitative PCR and immunohistochemistry. The studies suggest that isoquercitrin significantly reduces fasting blood glucose levels, enhances the body's capacity to regulate blood glucose and insulin resistance, and facilitates renal pathology and renal function. Simultaneously, it can lower blood lipids (total cholesterol and triglyceride) and improve the risk factors of DN. Meanwhile, isoquercitrin suppressed the expression of SGLT2 in renal tissues of DN mouse models. In vitro, real-time quantitative PCR and Western blot were used to detect the expression of SGLT2 in the human renal tubular epithelial (HK-2) cells. The effects of isoquercitrin on the survival rate and glucose uptake capacity of HK-2 cells were determined by Cell-Counting-Kit-8 and glucose uptake methods. The results demonstrate that isoquercitrin suppressed the up-regulation of SGLT2 mRNA and protein in high-glucose-induced HK-2 cells. Additionally, isoquercitrin inhibited glucose uptake in HK-2 cells and mitigated high-sugar-induced damage. Thus, this study has concluded that isoquercitrin exhibits hypoglycemic and renal protective effects by inhibiting the SGLT2 pathway, indicating its potential as a promising anti-DN drug deserving further clinical investigation.

Renal hemodynamics damage, an important driving mechanism of diabetic nephropathy (DN), is related to many abnormal endothelial released molecules, such as endothelial nitrogen monoxide synthase (eNOS) and endothelin-1 (ET-1), caused by glomerular endothelial cells dysfunction. Apelin, as the endogenous ligand for APJ, was reported to be associated with endothelial cell dysfunction in diabetes. Therefore, it is hypothesized that apelin/APJ increased renal perfusion in DN through regulating endothelial released molecules. Diabetic models were replicated via injecting STZ intraperitoneally (40 mg/kg/day) for 5 consecutive days. Apelin-13 was infused with micro-osmotic pump at 30 μg/kg/day for 4 weeks. The results showed that apelin increased renal blood flow by increasing phosphorylated eNOS and decreasing ET-1 in diabetic mice, which were cancelled in endothelial-specific APJ knockout mice or whole-body large conductance Ca2 +-activated K+ (BKCa) channel knockout rats. Additionally, apelin/APJ activated BKCa channel via increasing expression of BKCa subunits through PI3K/AKT/GSK-3β/Nrf2 pathway but not increasing intracellular Ca2+ concentration under high glucose conditions. In conclusion, this study revealed that apelin/APJ increased renal blood flow in early phase of DN via increasing p-eNOS and decreasing ET-1 in glomerular endothelial cells dependent on PI3K/AKT/GSK-3β/Nrf2 pathway induced expression of BKCa subunits.

Fibrosis is the terminal pathology of chronic illness in many organs, marked by excessive accumulation of extracellular matrix proteins. These changes influence organ function, ultimately resulting in organ failure. Although significant progress has been achieved in comprehending the molecular pathways responsible for fibrosis in the last decades, effective and approved clinical therapies for the condition are still lacking. Andrographolide is a diterpenoid isolated and purified mainly from the aboveground parts of the Andrographis paniculata plant, which possesses good effects of purging heat, detoxifying, antibacterial and anti-inflammatory. In-depth research has gradually confirmed the anticancer, antioxidant, antiviral and other effects of Andro so that it can play a preventive and therapeutic role in various diseases. Over the past few years, an increasing number of research findings have indicated that Andro exerts antifibrotic effects in various organs by acting on transforming growth factor-β/small mother against decapentaplegic protein, mitogen-activated protein kinases, nuclear factor-E2-related factor 2, nuclear factor kappa-B and other signalling molecules to inhibit inflammation, oxidative stress, epithelial-mesenchymal transition, fibroblast activation and collagen buildup. This review presents a compilation of findings regarding the antifibrotic impact of Andro in tissue and cell models in vitro and in vivo. Emphasis is placed on the potential therapeutic benefits of Andro in diseases related to organ fibrosis. Existing studies and cutting-edge technologies on Andro pharmacokinetics, toxicity and bioavailability are briefly discussed to provide evidence for accelerating its clinical conversion and adoption.

Linggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD.

This study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG.

LGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage.

Treatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis.

Our data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.

Diabetic nephropathy is the leading cause of end-stage kidney disease, and the association between impaired autophagy and kidney structure damage in diabetes is well known. Diets enriched with polyunsaturated fatty acids (PUFAs) have been the subject of numerous studies on preventing and treating various metabolic disorders. The results of these studies suggest that n-3 PUFA may have a renoprotective effect, reducing the structural damage to the kidneys associated with DM. We hypothesized that the activation of autophagy partly mediates the potential protective effect of n-3 PUFA on diabetic kidneys. Wistar rats were randomly divided into four groups according to the type of diet: control (C) and diabetic (STZ) groups received food including 0.5 % linseed oil and 2 % sunflower oil with an n-6/n-3 ratio of 7; the STZ+N6 group received a diet with 2.5 % sunflower oil with an n-6/n-3 ratio of 60; and the STZ+N3 group received a diet containing 2.5 % fish oil with an n-6/n-3 ratio of 1, with the addition of eicosapentaenoic acid (EPA) and 19 % docosahexaenoic acid (DHA). All rats, except for those in the C group, had diabetes induced by an intraperitoneal injection of streptozotocin. We conducted histological and immunohistochemical assessments to determine the effects of different n-6/n-3 PUFA dietary ratios on the expression levels of different autophagy markers in the kidney of the rats. The results indicate significant effects of n-3 and n-6 PUFA supplementation on the expression of different autophagy markers in the renal cortex of the diabetic rats. In particular, n-6 PUFA supplementation increased LC3B expression while simultaneously decreasing Rab7 expression; meanwhile, n-3 PUFA supplementation resulted in a decreased expression of LAMP2A and Rab7. Moreover, n-3 PUFA supplementation prevented an increase in BECL1 and p62, that was observed in kidneys from diabetic and diabetic n-3 supplemented animals. These results point to the complex interactions of fatty acids and autophagy during the development of diabetic kidney disease, which should be taken into account in future therapeutic approaches.

Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis.

This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein.

In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1.

CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Diabetic kidney disease (DKD) is a prominent complication arising from diabetic microangiopathy, and its prevalence and renal impact have placed it as the primary cause of end-stage renal disease. Traditional Chinese Medicine (TCM) has the distinct advantage of multifaceted and multilevel therapeutic attributes that show efficacy in improving clinical symptoms, reducing proteinuria, protecting renal function, and slowing DKD progression. Over recent decades, extensive research has explored the mechanisms of TCM for preventing and managing DKD, with substantial studies that endorse the therapeutic benefits of TCM compounds and single agents in the medical intervention of DKD.

This review lays the foundation for future evidence-based research efforts and provide a reference point for DKD investigation.

The relevant literature published in Chinese and English up to 30 June 2023, was sourced from PubMed, Cochrane Library, VIP Database for Chinese Technical Periodicals (VIP), Wanfang Data, CNKI, and China Biology Medicine disc (CBM). The process involved examining and summarizing research on TCM laboratory tests and clinical randomized controlled trials for DKD treatment.

The TCM intervention has shown the potential to inhibit the expression of inflammatory cytokines and various growth factors, lower blood glucose levels, and significantly affect insulin resistance, lipid metabolism, and improved renal function. Furthermore, the efficacy of TCM can be optimized by tailoring personalized treatment regimens based on the unique profiles of individual patients. We anticipate further rigorous and comprehensive clinical and foundational investigations into the mechanisms underlying the role of TCM in treating DKD.

As the global incidence of diabetes rises and diagnoses among younger patients increase, transplant centers worldwide are encountering more organ donors with diabetes. This study examined 80 donors and 160 recipients, including 30 donors with diabetes (DD) and their 60 recipients (DDR). The control group comprised 50 non-diabetic donors (ND) and 100 recipients (NDR). We analyzed clinical, biochemical, and pathological data for both diabetic and control groups, using logistic regression to identify risk factors for delayed graft function (DGF) after kidney transplantation. Results showed that pre-procurement blood urea nitrogen levels were significantly higher in DD [18.20 ± 10.63 vs. 10.86 ± 6.92, p = 0.002] compared to ND. Renal pathological damage in DD was notably more severe, likely contributing to the higher DGF incidence in DDR compared to NDR. Although DDR had poorer renal function during the first three months post-transplant, both groups showed similar renal function thereafter. No significant differences were observed in 1-year or 3-year mortality rates or graft failure rates between DDR and NDR. Notably, according to the Renal Pathology Society (RPS) grading system, kidneys from diabetic donors with a grade > IIb are associated with significantly lower postoperative survival rates. Recipient gender [OR: 5.452 (1.330-22.353), p = 0.013] and pre-transplant PRA positivity [OR: 34.879 (7.698-158.030), p < 0.001] were identified as independent predictors of DGF in DDR. In conclusion, transplant centers may consider utilizing kidneys from diabetic donors, provided they are evaluated pathologically, without adversely impacting recipient survival and graft failure rates.

We investigated the link between ferroptosis and the miR-223-3p/inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) pathway in diabetic kidney disease (DKD). Blood samples from DKD patients and healthy controls were analysed for iron ions, calcium ions, and lipid peroxidation. High-glucose-induced glomerular endothelial cells were used to simulate DKD. MiR-223-3p overexpression or silencing was achieved using adenoviruses, affecting ferroptosis regulators (glutathione peroxidase 4 [GPX4], cystine/glutamate transporter (xCT), and long-chain acyl-CoA synthetase 4 [ACSL4]) and ITPR3. DKD patients showed elevated levels of iron ions, calcium ions, and lipid peroxidation. High glucose downregulated miR-223-3p, reducing xCT and GPX4 expression and increasing ACSL4 expression. MiR-223-3p was confirmed to target ITPR3 through luciferase reporter assay. MiR-223-3p overexpression reversed high-glucose-induced effects on ferroptosis markers and ITPR3 expression. In summary, high glucose levels decreased miR-223-3p expression, leading to increased calcium ion levels and ferroptosis, potentially through ITPR3 modulation. These findings provide insights into the mechanisms underlying DKD and its potential therapeutic targets.

The clinical trajectory of normoalbuminuric chronic kidney disease (CKD), particularly in the absence of diabetes, has not yet been well-studied. This study evaluated the association of kidney and cardiovascular outcomes with levels of albuminuria in a cohort of patients with nondiabetic CKD.

Prospective cohort study.

1,463 adults with nondiabetic CKD without known glomerulonephritis and diagnosed with hypertensive nephrosclerosis or unknown cause of CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Albuminuria stage at study entry.

Primary outcome: Composite kidney (halving of estimated glomerular filtration rate [eGFR], kidney transplantation, or dialysis), Secondary outcomes: (1) eGFR slope, (2) composite cardiovascular disease events (hospitalization for heart failure, myocardial infarction, stroke, or all-cause death), (3) all-cause death.

Linear mixed effects and Cox proportional hazards regression analyses.

Lower levels of albuminuria were associated with female sex and older age. For the primary outcome, compared with normoalbuminuria, those with moderate and severe albuminuria had higher rates of kidney outcomes (adjusted hazard ratio [AHR], 3.3 [95% CI, 2.4-4.6], and AHR, 8.6 [95% CI, 6.0-12.0], respectively) and cardiovascular outcomes (AHR, 1.5 [95% CI, 1.2-1.9], and AHR, 1.5 [95% CI, 1.1-2.0], respectively). Those with normoalbuminuria (<30μg/mg; n=863) had a slower decline in eGFR (-0.46mL/min/1.73m2 per year) compared with those with moderate (30-300μg/mg, n=372; 1.41mL/min/1.73m2 per year) or severe albuminuria (>300μg/mg, n=274; 2.63mL/min/1.73m2 per year). In adjusted analyses, kidney outcomes occurred, on average, sooner among those with moderate (8.6 years) and severe (7.3 years) albuminuria compared with those with normoalbuminuria (9.3 years) whereas the average times to cardiovascular outcomes were similar across albuminuria groups (8.2, 8.1, and 8.6 years, respectively).

Self-report of CKD etiology without confirmatory kidney biopsies; residual confounding.

Participants with normoalbuminuric nondiabetic CKD experienced substantially slower CKD progression but only modestly lower cardiovascular risk than those with high levels of albuminuria. These findings inform the design of future studies investigating interventions among individuals with lower levels of albuminuria.

Diabetes and hypertension are the leading causes of chronic kidney disease (CKD). Urine albumin levels are associated with cardiovascular and kidney disease outcomes among individuals with CKD. However, previous studies of long-term clinical outcomes in CKD largely included patients with diabetes. As well, few studies have evaluated long-term outcomes across different levels of urine albumin among people without diabetes. In this study, we found individuals with nondiabetic CKD and low urine albumin had much slower decline of kidney function but only a modestly lower risk of a cardiovascular events compared with those with high levels of urine albumin. Individuals with low urine albumin were much more likely to have a cardiovascular event than progression of their kidney disease. These findings inform the design of future studies investigating treatments among individuals with lower levels of albuminuria.

To identify potential biomarkers and explore the mechanisms underlying diabetic nephropathy (DN) by integrating machine learning, Mendelian randomization (MR) and experimental validation.

Microarray and RNA-sequencing datasets (GSE47184, GSE96804, GSE104948, GSE104954, GSE142025 and GSE175759) were obtained from the Gene Expression Omnibus database. Differential expression analysis identified the differentially expressed genes (DEGs) between patients with DN and controls. Diverse machine learning algorithms, including least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and random forest, were used to enhance gene selection accuracy and predictive power. We integrated summary-level data from genome-wide association studies on DN with expression quantitative trait loci data to identify genes with potential causal relationships to DN. The predictive performance of the biomarker gene was validated using receiver operating characteristic (ROC) curves. Gene set enrichment and correlation analyses were conducted to investigate potential mechanisms. Finally, the biomarker gene was validated using quantitative real-time polymerase chain reaction in clinical samples from patients with DN and controls.

Based on identified 314 DEGs, seven characteristic genes with high predictive performance were identified using three integrated machine learning algorithms. MR analysis revealed 219 genes with significant causal effects on DN, ultimately identifying one co-expressed gene, carbonic anhydrase II (CA2), as a key biomarker for DN. The ROC curves demonstrated the excellent predictive performance of CA2, with area under the curve values consistently above 0.878 across all datasets. Additionally, our analysis indicated a significant association between CA2 and infiltrating immune cells in DN, providing potential mechanistic insights. This biomarker was validated using clinical samples, confirming the reliability of our findings in clinical practice.

By integrating machine learning, MR and experimental validation, we successfully identified and validated CA2 as a promising biomarker for DN with excellent predictive performance. The biomarker may play a role in the pathogenesis and progression of DN via immune-related pathways. These findings provide important insights into the molecular mechanisms underlying DN and may inform the development of personalized treatment strategies for this disease.

Cell senescence and metabolic reprogramming are significant features of diabetic kidney disease (DKD). However, the underlying mechanisms between cell senescence and metabolic reprogramming are poorly defined. Here, we report that retinoid X receptor α (RXRα), a key nuclear receptor transcription factor, regulates cell senescence and metabolic reprogramming in DKD. Through high-throughput sequencing, bioinformatic analysis and experimental validation, we confirmed the critical role of RXRα in promoting cell senescence and metabolic dysregulation in renal tubular epithelial cells (RTECs) induced by lipid overload. In vivo, in situ injection of AAV9-shRxra into the kidney reduced proteinuria, RTECs senescence and insulin resistance in DKD mice. In vitro, knockdown of RXRα markedly improved G2/M phase arrest and suppressed the expression of senescence-associated secretory phenotypes (SASPs). Protein-protein interaction (PPI) analysis and unbiased bioinformatics were employed to identify the direct interactions between RXRα and the mineralocorticoid receptor (MR), which were subsequently validated through coimmunoprecipitation. Gene network analysis revealed the collaborative regulatory role of RXRα and MR in RTECs senescence. In an accelerated aging mouse model, treatment with a MR antagonist has been shown to inhibite the RXRα/MR signaling, improve RTECs senescence, and reduce interstitial fibrosis and lipid deposition in the kidneys. These findings indicate that inhibition of RXRα/MR signaling could alleviate cell senescence during metabolic disorders. Thus, our study revealed that RXRα/MR signaling serves as a critical regulatory factor mediating the crosstalk between cell senescence and metabolic reprogramming, shedding light on a novel mechanism for targeting cell senescence and metabolic dysregulation in DKD.

There is no evidence on the associations between persistent organic pollutants (POPs) and the incidence of chronic kidney disease (CKD) in the Chinese rural population. We aimed to investigate the individual and mixed effects of 22 POPs on the prevalence and incidence of CKD, and the joint effects of POPs and abnormal glucose metabolism as well as the modification effects of healthy lifestyle on these associations. A total of 2775 subjects, including 925 subjects with normal plasma glucose (NPG) and 925 subjects with prediabetes (PDM) and type 2 diabetes mellitus (T2DM), were enrolled from the Henan Rural Cohort Study. Logistic regression and quantile g-computation were performed to assess the individual and mixed effects of POPs on the risk of CKD. Joint effects of POPs and abnormal glucose metabolism status, as well as the modification effects of lifestyle on CKD were assessed. After 3-year follow-up, an increment of ln-o,p'-DDT was related to an elevated risk of CKD prevalence. Positive associations of p,p'-DDE and β-BHC with CKD incidence were observed (P < 0.05). In addition, participants with high levels of ∑POPs were associated elevated incidence risk of CKD (OR: 1.217, 95%CI: 1.008-1.469). One quartile increase in POPs mixture was associated with the increased incidence of CKD among T2DM patients (P < 0.05). Further, a higher risk of CKD was observed among PDM and T2DM patients with high levels of o,p'-DDT, p,p'-DDE, β-BHC, and ∑POPs than NPG subjects with low levels of pollutants. In addition, interactive effects of ∑POPs and lifestyle score on CKD incidence were found. Individual and mixed exposure to POPs increased the prevalence and incidence of CKD, and glucose metabolic status exacerbated the risk of CKD resulting from such exposures. Further, the modifying effects of lifestyle were observed, highlighting the importance of precision prevention for high-risk CKD population and healthy lifestyle intervention measures.

Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus, characterized by complex pathogenesis that involves numerous molecules and signaling pathways. Among these, CD2 glycoprotein and CD44 play pivotal roles in cell adhesion, signal transduction, and inflammatory responses, potentially contributing significantly to the onset and progression of DN. This study aimed to investigate the central features of CD2 glycoprotein and CD44 in preventing diabetic nephropathy. To achieve this, kidney tissue sample data from DN patients were sourced from a public gene expression database. The roles of CD2 glycoprotein and CD44 within the PPI network were then analyzed, focusing on their interactions with other related genes. WGCNA analysis identified several significant gene modules associated with DN, including CD2 glycoprotein and CD44. PPI network analysis showed that these two proteins had a high degree of connectivity in the network, suggesting that they may be central regulatory molecules of DN. Further functional enrichment analysis revealed the potentially important role of CD2 glycoprotein and CD44 in diabetic nephropathy.

Diabetic Nephropathy is one of the most severe complications of Diabetes Mellitus and the main cause of end-stage kidney disease worldwide. Despite the therapies available to control blood glucose and blood pressure, many patients continue to suffer from progressive kidney damage. Chronic hyperglycemia is the main driver of changes observed in diabetes; however, it was recently discovered that inflammation and oxidative stress contribute to the development and progression of kidney damage. Therefore, it is important to search for new pharmacological therapies that stop the progression of DN. Sodium tungstate (NaW) is an effective short and long-term antidiabetic agent in both type 1 and type 2 diabetes models.

In this study, the effect of NaW on proinflammatory signalling pathways, proinflammatory proteins and fibrosis in the streptozotocin (STZ)-induced type 1 diabetic rat model was analysed using histological analysis, western blotting and immunohistochemistry.

NaW treatment in diabetic rats normalize parameters such as glycemia, glucosuria, albuminuria/creatinuria, glomerular damage, and tubulointerstitial damage. NaW decreased the proinflammatory signaling pathway NF-κB, inflammatory markers (ICAM-1, MCP-1 and OPN), profibrotic pathways (TGFβ1/Smad2/3), reduced epithelial-mesenchymal transition (α -SMA), and decreased renal fibrosis (type IV collagen).

NaW could be an effective drug therapy for treating human diabetic nephropathy.

Renal interstitial fibrosis (RIF) is a significant pathological change in diabetic kidney disease (DKD) that can be induced by endothelial-to-mesenchymal transition (EndMT). Lymphangiogenesis, mediated by the vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) pathway, plays a crucial role in the development of RIF in DKD. Although numerous studies have demonstrated the efficacy of empagliflozin in treating renal injury, its effects on lymphangiogenesis in DKD-related RIF and the underlying mechanisms remain unclear. In the present study, significant lymphangiogenesis was assessed in the renal interstitium of patients with DKD. We subsequently explored the relationship between DKD-related RIF and lymphangiogenesis in mouse models, high-glucose (HG)-stimulated renal HK-2 cell lines, and human lymphatic endothelial cells (hLECs). Additionally, we evaluated the effects of empagliflozin on these processes. The results revealed that HG induces lymphangiogenesis, which exacerbates RIF by promoting inflammatory responses. Furthermore, hLECs directly contributed to the progression of DKD-related RIF through EndMT. Further analysis revealed that tubular epithelial cells (TECs) act as effector cells for VEGF-C, with the epithelial-to-mesenchymal transition (EMT) of TECs occurring concurrently with the EndMT of lymphatic vessels. Empagliflozin inhibited RIF in DKD by suppressing the VEGF-C/VEGFR3 pathway and reducing lymphangiogenesis. In conclusion, this study elucidates the interplay between lymphangiogenesis, EndMT, and RIF in DKD and provides new insights into the mechanism by which empagliflozin treats DKD.

The activity of sodium glucose co-transporter 2 (SGLT2) has always been an important parameter influencing chronic kidney disease in type-2 diabetic patients. Herein, we have meticulously designed, synthesized, and evaluated several novel steroidal pyrimidine molecules that possess the capability to successfully bind to the SGLT2 protein and inhibit its activity, thereby remedying kidney-related ailments in diabetic patients. The lead steroidal pyrimidine compounds were selected after virtually screening from a library of probable N-heterocyclic steroidal scaffolds. A nano-catalyzed synthetic route was also explored for the synthesis of the steroidal pyrimidine analogs demonstrating an environmentally benign protocol. Extensive in vitro investigations encompassing SGLT2 screening assays and cell viability assessments were conducted on the synthesized compounds. Among the steroidal pyrimidine derivatives evaluated, compound 9a exhibited the highest SGLT2 inhibition activity and underwent further scrutiny. Western blot analysis was employed to determine the impact of 9a on inflammatory and fibrotic proteins, aiming to elucidate its mechanism of action. Additionally, in silico analyses were performed to illuminate the structural dynamics and molecular interaction mechanism of 9a. The overall investigation is crucial for advancing the development of the next generation of anti-diabetic drugs.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes characterized by inflammation, oxidative stress, and renal fibrosis. Asiaticoside (AC) exhibits anti-inflammatory, antioxidant, and anti-fibrotic properties, suggesting potential therapeutic benefits for DN. This study aimed to investigate the protective effects of AC against DN and elucidate the underlying mechanisms involving the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) antioxidant pathway.

To investigate the renoprotective effects of AC against DN and elucidate the role of the NRF2/HO-1 pathway.

The effects of AC on high glucose (HG)-induced proliferation, inflammation, oxidative stress, and fibrosis were evaluated in rat glomerular mesangial cells (HBZY-1) in vitro. A streptozotocin-induced DN rat model was established to assess the in vivo impact of AC on renal injury, inflammation, oxidative stress, and fibrosis. The involvement of the NRF2/HO-1 pathway was examined using pharmacological inhibition studies in the cell model.

AC inhibited HG-induced HBZY-1 cell proliferation and significantly improved various indicators of DN in rats, including reduced body weight, and elevated blood glucose, serum creatinine, blood urea nitrogen, and 24-h urine protein. Both in vitro and in vivo studies demonstrated that AC decreased inflammation and oxidative stress by reducing interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, reactive oxygen species, and malondialdehyde levels while increasing superoxide dismutase activity. Additionally, AC suppressed the expression of fibrogenic markers such as collagen I, collagen IV, and fibronectin. AC activated NRF2 expression in the nucleus and increased HO-1 and NAD(P)H dehydrogenase (Quinone) 1 protein expression in renal tissues and HG-induced HBZY-1 cells.

AC improves DN by reducing inflammation, oxidative stress, and fibrosis through the activation of the NRF2/HO-1 signaling pathway. These findings not only highlight AC as a promising therapeutic candidate for DN but also underscore the potential of targeting the NRF2/HO-1 pathway in developing novel treatments for other chronic kidney diseases characterized by oxidative stress and inflammation.

A new population of peripheral helper T (Tph) cells has been identified and contributed to various autoimmune diseases. Tph cells can secrete interleukin-21 (IL-21), interferon (IFN) and C-X-C motif chemokine ligand 13 (CXCL13) to moderate renal disease. Moreover, Tph cells can congregate in huge numbers and immerse within inflamed tissue. Compared to Tfh cells, Tph cells express high programmed cell death protein 1 (PD-1), major histocompatibility complex II (MHC-II), C-C chemokine receptor 2 (CCR2) and C-C chemokine receptor 5 (CCR5) but often lack expression of the chemokine receptor C-X-C chemokine receptor 5 (CXCR5). They display features distinct from other T cells, which are uniquely poised to promote responses and antibody production of B cells within pathologically inflamed non-lymphoid tissues and a key feature of Tph cells. In this review, we summarize recent findings on the role of Tph cells in chronic kidney disease, acute kidney injury, kidney transplantation and various renal diseases.

This cross-sectional study investigated the relationship between dietary antioxidant indices and kidney function indicators in 240 outpatient adults with type 2 diabetes. Dietary intake was assessed using three 24-h dietary recalls. Dietary total antioxidant capacity (DTAC), dietary antioxidant index (DAI), and dietary antioxidant quality score (DAQS) were obtained. Indicators of kidney function, including serum creatinine, urea, blood urea nitrogen (BUN), and glomerular filtration rate (GFR), were extracted from medical records. After adjustment, the highest DAI tertile had lower serum creatinine (0.98 ± 0.27 vs 1.03 ± 0.32 mg/dL, P < 0.001), reduced urea (30.97 ± 8.75 vs 34.07 ± 14.45 mg/dL, P = 0.005), and higher GFR (85.16 ± 29.43 vs 74.16 ± 22.18 ml/min per 1·73 m2, P < 0.001) compared to the lowest tertile. The results of logistic regression analysis indicated a borderline significant inverse association of serum urea > 20 mg/dl with DTAC (odds ratio (OR):0.28; 95% CI: 0.07-1.09; Ptrend = 0.06). Multivariable linear regression analysis revealed a significant aligned correlation between DAQs and GFR (β: 0.20; P-value: 0.005) and a marginally significant direct relationship between DAI and GFR (β: 0.14; P-value: 0.06). However, no significant association was observed for DTAC with GFR (β:-0.02; P-value: 0.80). Diets with higher antioxidant capacity may be linked to improved kidney function in type 2 diabetes but our results did not support this strongly.

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis.