Genomics in Diabetic Kidney Disease: A 2024 Update.

Diabetic Kidney Disease (DKD) remains the leading cause of Chronic and End Stage Kidney Disease (ESKD) worldwide, with an increasing epidemiological burden. However, still, the disease awareness remains low, early diagnosis is difficult, and therapeutic management is ineffective. These might be attributed to the fact that DKD is a highly heterogeneous disease, with disparities and variability in clinical presentation and progression patterns. Besides environmental risk factors, genetic studies have emerged as a novel and promising tool in the field of DKD. Three decades ago, family studies first reported that inherited genetic factors might confer significant risk to DKD development and progression. During the past decade, genome-wide association studies (GWASs) screening the whole genome in large and multi-ethnic population-based cohorts identified genetic risk variants associated with traits defining DKD in both type 1 and 2 diabetes. Herein, we aim to summarize the existing data regarding the progress in the field of genomics in DKD, present how the revolution of GWAS expanded our understanding of pathophysiologic disease mechanisms and finally, suggest potential future directions.

Analysis of the microecological mechanism of diabetic kidney disease based on the theory of "gut-kidney axis": A systematic review.

Diabetic kidney disease (DKD) is one of the main microvascular complications of diabetes mellitus, as well as the leading cause of end-stage renal disease. Intestinal microbiota has emerged as a crucial regulator of its occurrence and development. Dysbiosis of the intestinal microbiota can disrupt the intestinal mucosal barrier, abnormal immunological response, reduction in short-chain fatty acid metabolites, and elevation of uremic toxins, all closely related to the occurrence and development of DKD. However, the underlying mechanisms of how intestinal microbiota and its metabolites influence the onset and progression of DKD has not been fully elucidated. In the current review, we will try to summarize the microecological mechanism of DKD by focusing on three aspects: the intestinal microbiota and its associated metabolites, and the "gut-kidney axis," and try to summarize therapies targeted at managing the intestinal microbiota, expecting to provide theoretical basis for the subsequent study of the relationship between intestinal homeostasis and DKD, and will open an emerging perspective and orientation for DKD treatment.

Association between hydration status and the risk and all-cause mortality of diabetic kidney disease.

BACKGROUND: This cohort study aimed to explore the relationship between hydration status and the risk of diabetic kidney disease (DKD) as well as all-cause death in DKD patients. METHODS: Weighted univariable and multivariable logistic regression models were used to explore the association between hydration status and DKD risk in diabetic population while weighted univariable and multivariable Cox regression models were used to identify the association between hydration status and all-cause mortality in DKD patients. Kaplan-Meier curve was plotted to present the survival probability of patients with different hydration status. Estimates were presented as odds ratio (OR), and hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The mean follow-up time was 79.74 (±1.89) months. There were 2041 participants with DKD, and 2889 participants without. At the end of the follow-up, 965 participants were alive. The risk of DKD was increased as the increase of osmolarity level (OR = 1.07, 95%CI: 1.05-1.08). The elevated risk of DKD was observed in patients with impending dehydration (OR = 1.49, 95%CI: 1.19-1.85) or current dehydration (OR = 2.69, 95%CI: 2.09-3.46). The association between increased osmolarty level and elevated risk of all-cause mortality in DKD patients was statistically different (HR = 1.02, 95%CI: 1.01-1.03). Current dehydration was correlated with increased all-cause mortality risk in DKD patients (HR = 1.27, 95%CI: 1.01-1.61). Compared to DKD patients with normal hydration, the survival probability of DKD patients with current dehydration was significant lower (p < 0.001). CONCLUSION: Increased osmolarity level was associated with increased risk of DKD and elevated risk of all-cause mortality in DKD patients.

Single-cell RNA sequencing in diabetic kidney disease: a literature review.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), and its pathogenesis has not been clarified. Current research suggests that DKD involves multiple cell types and extra-renal factors, and it is particularly important to clarify the pathogenesis and identify new therapeutic targets. Single-cell RNA sequencing (scRNA-seq) technology is high-throughput sequencing of the transcriptomes of individual cells at the single-cell level, which is an effective technology for exploring the development of diseases by comparing genetic information, reflecting the differences in genetic information between cells, and identifying different cell subpopulations. Accumulating evidence supports the role of scRNA-seq in revealing the pathogenesis of diabetes and strengthening our understanding of the molecular mechanisms of DKD. We reviewed the scRNA-seq data this time. Then, we analyzed and discussed the applications of scRNA-seq technology in DKD research, including annotation of cell types, identification of novel cell types (or subtypes), identification of intercellular communication, analysis of cell differentiation trajectories, gene expression detection, and analysis of gene regulatory networks, and lastly, we explored the future perspectives of scRNA-seq technology in DKD research.

RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling.

BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

Association between visceral adiposity index and incidence of diabetic kidney disease in adults with diabetes in the United States.

Visceral adiposity index (VAI) is a reliable indicator of visceral adiposity. However, no stu-dies have evaluated the association between VAI and DKD in US adults with diabetes. Theref-ore, this study aimed to explore the relationship between them and whether VAI is a good pr-edictor of DKD in US adults with diabetes. Our cross-sectional study included 2508 participan-ts with diabetes who were eligible for the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Univariate and multivariate logistic regression were used to an-alyze the association between VAI level and DKD. Three models were used to control for pot-ential confounding factors, and subgroup analysis was performed for further verification. A tot-al of 2508 diabetic patients were enrolled, of whom 945 (37.68%) were diagnosed with DKD. Overall, the VAI was 3.36 ± 0.18 in the DKD group and 2.76 ± 0.11 in the control group. VAI was positively correlated with DKD (OR = 1.050, 95% CI 1.049, 1.050) after fully adjusting for co-nfounding factors. Compared with participants in the lowest tertile of VAI, participants in the highest tertile of VAI had a significantly increased risk of DKD by 35.9% (OR = 1.359, 95% CI 1.355, 1.362). Through subgroup analysis, we found that VAI was positively correlated with the occurrence of DKD in all age subgroups, male(OR = 1.043, 95% CI 1.010, 1.080), participants wit-hout cardiovascular disease(OR = 1.038, 95% CI 1.011, 1.069), hypertension (OR = 1.054, 95% CI 1.021, 1.090), unmarried participants (OR = 1.153, 95% CI 1.036, 1.294), PIR < 1.30(OR = 1.049, 95% CI 1.010, 1.094), PIR ≧ 3 (OR = 1.085, 95% CI 1.021, 1.160), BMI ≧ 30 kg/m2 (OR = 1.050, 95% CI 1.016, 1.091), former smokers (OR = 1.060, 95% CI 1.011, 1.117), never exercised (OR = 1.033, 95% CI 1.004, 1.067), non-Hispanic white population (OR = 1.055, 95% CI 1.010, 1.106) and non-Hipanic black population (OR = 1.129, 95% CI 1.033, 1.258). Our results suggest that elevated VAI levels are closely associated with the development of DKD in diabetic patients. VAI may be a simpl-e and cost-effective index to predict the occurrence of DKD. This needs to be verified in furt-her prospective investigations.

Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS-/- dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS-/- dbdb (diabetes), and eNOS-/- dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS-/- dbdb mice at Week 16 at 5 µg/g body weight in ~100 µL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS-/- dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD.

Real-World Clinical Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist on Mild-to-Moderate Diabetic Kidney Disease in Patients with Type 2 Diabetes: A Retrospective, Single-Arm Clinical Trial.

Background: Cardiovascular outcome trials indicate renal benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs); however, real-world efficacy and safety studies in Diabetic kidney disease (DKD) are scarce. Methods: This retrospective, single-arm real-world trial involved adults with DKD treated with GLP-1RA for at least 6 months. The primary endpoint was hemoglobin A1c (HbA1c) levels after 6 months. Results: This study included a total of 364 patients with DKD, 153 (42.0%) of whom were female. The median disease duration was 8.0 years, and the mean values of age, HbA1c level, body mass index, and the urinary albumin-to-creatinine ratio (UACR) were 52.1 years, 8.6%, 27.8 kg/m2, and 88.0 mg/g, respectively. Additionally, 73.6% and 26.4% of patients had mild and moderate DKD, respectively. Following 6 months of GLP-1RA treatment, the mean HbA1c level and UACR declined by 1.77% and 40.3%, respectively (both p < 0.001). Compared to their baseline values, patients exhibited significant improvements in 24-h urinary protein, estimated glomerular filtration rate (eGFR), fasting blood glucose, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (all p < 0.001). Patients with a disease duration of <10 years had more pronounced changes in the HbA1c level, UACR, and eGFR (all p < 0.001) than those with a disease duration of ≥10 years. Changes in SBP and DBP were more pronounced in patients also taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEis/ARBs) than in those not taking ACEis/ARBs, whereas the changes in UACR and eGFR did not significantly differ. Conclusion: Six-month GLP-1RA treatment improves glucose, blood pressure, lipids, and body weight in patients with mild-to-moderate DKD while slowing down kidney disease progression. It independently reduces proteinuria beyond ACEi/ARB impact, with early use yielding faster outcomes, supporting evidence-based practice.

Colquhounia root tablet improves diabetic kidney disease by regulating epithelial-mesenchymal transition via the PTEN/PI3K/AKT pathway.

Background: Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes mellitus that can lead to end-stage renal disease. Colquhounia root tablet (CRT) has shown therapeutic potential in treating DKD, but its efficacy and underlying mechanisms remain to be elucidated. Methods: A randomized controlled clinical trial was conducted on 61 DKD patients. The treatment group received CRT in addition to standard therapy, while the control group received standard therapy alone. Treatment efficacy and adverse events were evaluated after 3 months. Additionally, in vitro experiments using human renal tubular epithelial cells (HK-2) were performed to investigate the effect of CRT on high glucose (HG)-induced epithelial-mesenchymal transition (EMT) and the involvement of the PTEN/PI3K/AKT signaling pathway. Results: CRT treatment significantly improved proteinuria and increased the effective treatment rate in DKD patients compared to the control group, with no significant difference in adverse events. Moreover, CRT reversed HG-induced EMT in HK-2 cells, as evidenced by the downregulation of α-SMA and upregulation of E-cadherin at both mRNA and protein levels. Mechanistically, CRT increased PTEN expression and inhibited the PI3K/AKT pathway, similar to the effects of the PI3K inhibitor LY29400. The combination of CRT and LY29400 further enhanced PTEN mRNA expression under HG conditions. Conclusion: CRT effectively improves proteinuria in DKD patients and ameliorates HG-induced EMT in HK-2 cells. The underlying mechanism may involve the upregulation of PTEN and subsequent inhibition of the PI3K/AKT signaling pathway. These findings provide new insights into the therapeutic potential of CRT for DKD treatment.

Role of Extracellular Vesicle-Derived Noncoding RNAs in Diabetic Kidney Disease.

Background: Diabetic kidney disease (DKD), a metabolism-related syndrome characterized by abnormal glomerular filtration rate, proteinuria, and renal microangiopathy, is one of the most common forms of chronic kidney disease, whereas extracellular vesicles (EVs) have been recently evidenced as a novel cell communication player in DKD occurrence and progress via releasing various bioactive molecules, including proteins, lipids, and especially RNA, among which noncoding RNAs (including miRNAs, lncRNAs, and circRNAs) are the major regulators. However, the functional relevance of EV-derived ncRNAs in DKD is to be elucidated. Summary: Studies have reported that EV-derived ncRNAs regulate gene expression via a diverse range of regulatory mechanisms, contributing to diverse phenotypes related to DKD progression. Furthermore, there are already many potential clinical diagnostic and therapeutic studies based on these ncRNAs, which can be expected to have potential applications in clinical practice for EV-derived ncRNAs. Key Messages: In the current review, we summarized the mechanistic role of EVs in DKD according to biological function classifications, including inflammation and oxidative stress, epithelial-mesenchymal transition, cell death, and extracellular matrix deposition. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as diagnostic biomarkers and therapeutic targets in DKD.

Liraglutide ameliorates inflammation and fibrosis by downregulating the TLR4/MyD88/NF-kappaB pathway in diabetic kidney disease.

Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide, a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the TLR4/MyD88/NF-kappaB signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibited inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist - LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 weeks significantly improved the glomerular damage in streptozotocin-induced diabetic mice, and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4-/- diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis and inflammatory response in TLR4-/- diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs.

Practicalities and importance of assessing urine albumin excretion in type 2 diabetes: A cutting-edge update.

Type 2 diabetes (T2D) is associated with increased risk for chronic kidney disease (CKD). It is estimated that 40 % of people with diabetes have CKD, which consequently leads to increase in morbidity and mortality from cardiovascular diseases (CVDs). Diabetic kidney disease (DKD) is leading cause of CKD and end-stage renal disease (ESRD) globally. On the other hand, DKD is independent risk factor for CVDs, stroke and overall mortality. According to the guidelines, using spot urine sample and assessing urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are both mandatory methods for screening of CKD in T2D at diagnosis and at least annually thereafter. Diagnosis of CKD is confirmed by persistent albuminuria followed by a progressive decline in eGFR in two urine samples at an interval of 3 to 6 months. However, many patients with T2D remain underdiagnosed and undertreated, so there is an urgent need to improve the screening by detection of albuminuria at all levels of health care. This review discusses the importance of albuminuria as a marker of CKD and cardiorenal risk and provides insights into the practical aspects of methods for determination of albuminuria in routine clinical care of patients with T2D.

Prevalence and clinical determinants of rapid eGFR decline among patients with newly diagnosed type 2 diabetes.

BACKGROUND: Diabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in the western world. Rapid estimated glomerular filtration rate (eGFR) decline is an independent predictor of ESKD and death in the general population and in subjects with type 2 diabetes mellitus (T2D). AIM: We investigated in a large sample of subjects with newly diagnosed T2D the prevalence and clinical determinants of fast eGFR decline, taking advantage from the dataset of the Associazione Medici Diabetologi (AMD) Annals initiative. METHODS: The eGFR trajectories were evaluated by applying a linear mixed model for repeated measures (LMMRM) and rapid eGFR decline defined as an eGFR decline greater than 5 mL/min/1.73 m2 per year at 3 years. RESULTS: Among 105,163 (57.7% M) subjects with newly diagnosed T2D, 13,587 (12.9 %) subjects showed a rapid eGFR loss. The independent significant predictors were age, female gender, HbA1c, smoking, high baseline eGFR, albuminuria and retinopathy. CONCLUSION: Our study demonstrates that a significant percentage of newly diagnosed T2D subjects have a rapid eGFR decline. Given the association between dynamic changes in eGFR and the risk of ESKD or death, we suggest to include this variable in the definition of CKD.

Elucidating the Mechanism of Jisheng Shenqi Pills in the Treatment of Diabetic Kidney Disease: Network Pharmacology Combined with Experimental Verification.

BACKGROUND: While the annual incidence of diabetic kidney disease (DKD) has been soaring, the exact mechanisms underlying its onset and progression remain partially understood. OBJECTIVE: The present study delved into the underlying mechanisms of Jisheng Shenqi Pill (JSP) in the treatment of DKD. METHODS: The active constituents and prospective targets of JSP were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), while DKD-associated disease targets were obtained from the GeneCards database. Subsequently, Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the overlapping segment of drugs and disease targets. Meanwhile, a component-target-pathway network was constructed to identify pivotal components, targets, and pathways. Molecular docking and molecular dynamics simulation were also carried out to validate the binding efficacy of the pivotal components with the targets. Finally, animal experiments were conducted to corroborate the efficacy of the aforementioned targets and pathways. RESULTS: According to bioinformatics analysis, the primary targets included JUN, TNF, and BAX, while the pivotal pathways involved were AGE/RAGE and PI3K/AKT signaling cascades. In vivo experiments demonstrated that JSP effectively mitigated renal impairment in DKD by reducing renal inflammation and apoptosis. This effect was presumably achieved by modulating the AGERAGE axis and the PI3K/AKT signaling pathway. CONCLUSION: Our findings imply that JSP could ameliorate renal inflammation and apoptosis in DKD mice by modulating the AGE/RAGE axis and the PI3K/AKT signaling pathway. These findings provide valuable insights into traditional Chinese medicine-based treatments for DKD.

From bytes to nephrons: AI's journey in diabetic kidney disease.

Diabetic kidney disease (DKD) is a significant complication of type 2 diabetes, posing a global health risk. Detecting and predicting diabetic kidney disease at an early stage is crucial for timely interventions and improved patient outcomes. Artificial intelligence (AI) has demonstrated promise in healthcare, and several tools have recently been developed that utilize Machine Learning with clinical data to detect and predict DKD. This review aims to explore the current landscape of AI and machine learning applications in DKD, specifically examining existing literature on risk scores and machine learning approaches for predicting DKD development. A literature search was conducted using Medline (PubMed), Google Scholar, and Scopus databases until July 2023. Relevant keywords were used to extract studies that described the role of AI in DKD. The review revealed that AI and machine learning have been successfully used to predict DKD progression, outperforming traditional risk score models. Artificial intelligence-driven research for DKD extends beyond prediction models, offering opportunities for integrating genetic and epigenetic data, advancing understanding of the disease's molecular basis, personalizing treatment strategies, and fostering the development of novel drugs. However, challenges remain, including the requirement for large datasets and the lack of standardization in AI-driven tools for DKD. Artificial intelligence and machine learning have the potential to revolutionize the management and care of DKD patients, surpassing the limitations of traditional methods reliant on existing knowledge. Future research should address the challenges associated with AI and machine learning in DKD and focus on developing AI-driven tools for clinical practice.

A new strategy for Astragaloside IV in the treatment of diabetic kidney disease: Analyzing the regulation of ferroptosis and mitochondrial function of renal tubular epithelial cells.

In China, the Astragalus membranaceus root is used to treat chronic kidney disease. Astragaloside IV (AS-IV), the primary bioactive compound, exhibits anti-inflammatory and antioxidative properties; however, its renoprotective mechanism in diabetic kidney disease (DKD) remains unclear. The study aimed to investigate the protective effects of AS-IV on DKD revealing the underlying mechanisms. We established an early diabetic rat model by feeding a high-fat diet and administering low-dose streptozotocin. Twelve weeks post-treatment, renal function was evaluated using functional assays, histological analyses, immunohistochemistry, western blotting, and transmission electron microscopy. HK-2 cells exposed to high glucose conditions were used to examine the effect of AS-IV on oxidative stress, iron levels, reactive oxygen species (ROS), and lipid peroxidation. Network pharmacology, proteomics, molecular docking, and molecular dynamics simulation techniques were employed to elucidate the role of AS-IV in DKD. The results revealed that AS-IV effectively enhanced renal function and mitigated disease pathology, oxidative stress, and ferroptosis markers in DKD rats. In HK-2 cells, AS-IV lowered the levels of lipid peroxides, Fe2+, and glutathione, indicating the repair of ferroptosis-related mitochondrial damage. AS-IV reduced mitochondrial ROS while enhancing mitochondrial membrane potential and ATP production, indicating its role in combating mitochondrial dysfunction. Overall, in silico analyses revealed that AS-IV interacts with HMOX1, FTH1, and TFR1 proteins, supporting its efficacy in alleviating renal injury by targeting mitochondrial dysfunction and ferroptosis. AS-IV may play a renoprotective role by regulating mitochondrial dysfunction and inhibiting. HMOX1/FTH1/TFR1-induced ferroptosis. Accordingly, AS-IV could be developed for the clinical treatment of DKD-related renal injury.

Inhibition of TFEB deacetylation in proximal tubular epithelial cells (TECs) promotes TFEB activation and alleviates TEC damage in diabetic kidney disease.

The inhibition of the autophagolysosomal pathway mediated by transcription factor EB (TFEB) inactivation in proximal tubular epithelial cells (TECs) is a key mechanism of TEC injury in diabetic kidney disease (DKD). Acetylation is a novel mechanism that regulates TFEB activity. However, there are currently no studies on whether the adjustment of the acetylation level of TFEB can reduce the damage of diabetic TECs. In this study, we investigated the effect of Trichostatin A (TSA), a typical deacetylase inhibitor, on TFEB activity and damage to TECs in both in vivo and in vitro models of DKD. Here, we show that TSA treatment can alleviate the pathological damage of glomeruli and renal tubules and delay the DKD progression in db/db mice, which is associated with the increased expression of TFEB and its downstream genes. In vitro studies further confirmed that TSA treatment can upregulate the acetylation level of TFEB, promote its nuclear translocation, and activate the expression of its downstream genes, thereby reducing the apoptosis level of TECs. TFEB deletion or HDAC6 knockdown in TECs can counteract the activation effect of TSA on autophagolysosomal pathway. We also found that TFEB enhances the transcription of Tfeb through binding to its promoter and promotes its own expression. Our results, thus, provide a novel therapeutic mechanism for DKD that the alleviation of TEC damage by activating the autophagic lysosomal pathway through upregulating TFEB acetylation can, thus, delay DKD progression.

Efficacy and safety of the traditional Chinese formula Shengjiang powder combined with conventional therapy in the treatment of diabetic kidney disease: a systematic review and meta-analysis.

Objective: To investigate the efficacy and safety of Shengjiang powder as a treatment for DKD. Methods: A comprehensive search was performed in eight databases from their inception to December 30, 2023, to identify relevant RCTs. The inclusion criteria were diagnosis of DKD and intervention including TCM that contained Shengjiang powder. Two researchers independently conducted literature screening and data extraction, utilizing the Rob2 tool and GRADE to assess the quality of the RCTs. Meta-analysis was carried out using RevMan 5.4.1 and Stata 15.0. Results: As a result of the search, 23 RCTs comprising 1,682 patients. The interventions resulted in significant reductions in all the assessed indicators: 24-h urinary protein, UAER, mALB, BUN, Scr, FBG, 2hPG, HbA1c, total cholesterol, and Triglycerides. Together the results showed that Shengjiang powder, in conjunction with conventional therapy, is an effective treatment of DKD. Subgroup analyses, considering duration, stage, blood glucose control levels, baseline blood glucose levels, and baseline Scr levels indicated that shorter duration treatment had a greater effect on UAER, 2hPG, and HbA1c. Additionally, Shengjiang powder was more effective in reducing 24-h urinary protein, Scr, and 2hPG in stage IV patients compared to corresponding values at other stages. However, with respect to FBG, the treatment was more effective in stage II/III. Shengjiang powder also, reduced Scr levels significantly in patients with higher baseline Scr and reduced urinary protein excretion with stricter blood glucose control. The interventions had additional lipid-regulating effects in cases with looser blood glucose control and led to a remarkable reduction in BUN and Scr levels in patients with FBG > 11.1 mmol/L. Conclusion: Shengjiang powder may supplement conventional therapy, thus benefiting DKD patients in terms of reducing urinary protein, stabilizing kidney function, and improving blood glucose and lipid metabolism. Considering the significant heterogeneity among studies and limited quality of some reports, our conclusions need to be further verified through analyses utilizing larger, multi-center samples of higher quality. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024490795.

The role of metabolic memory in diabetic kidney disease: identification of key genes and therapeutic targets.

Diabetic kidney disease (DKD) is characterized by complex pathogenesis and poor prognosis; therefore, an exploration of novel etiological factors may be beneficial. Despite glycemic control, the persistence of transient hyperglycemia still induces vascular complications due to metabolic memory. However, its contribution to DKD remains unclear. Using single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, we clustered 12 cell types and employed enrichment analysis and a cell‒cell communication network. Fibrosis, a characteristic of DKD, was found to be associated with metabolic memory. To further identify genes related to metabolic memory and fibrosis in DKD, we combined the above datasets from humans with a rat renal fibrosis model and mouse models of metabolic memory. After overlapping, NDRG1, NR4A1, KCNC4 and ZFP36 were selected. Pharmacology analysis and molecular docking revealed that pioglitazone and resveratrol were possible agents affecting these hub genes. Based on the ex vivo results, NDRG1 was selected for further study. Knockdown of NDRG1 reduced TGF-ß expression in human kidney-2 cells (HK-2 cells). Compared to that in patients who had diabetes for more than 10 years but not DKD, NDRG1 expression in blood samples was upregulated in DKD patients. In summary, NDRG1 is a key gene involved in regulating fibrosis in DKD from a metabolic memory perspective. Bioinformatics analysis combined with experimental validation provided reliable evidence for identifying metabolic memory in DKD patients.