Pathophysiology Of Diabetic Kidney Disease Research Articles

#444 Novel MRI filtration fraction method to assess glomerular hemodynamics in diabetic kidney disease

Abstract Background and Aims Filtration fraction (FF) is the ratio of the glomerular filtration rate (GFR) to renal plasma flow (RPF) and is therefore an important measure of glomerular hemodynamics. The gold standard method to assess effective RPF is renal clearance of para-aminohippuric acid (PAH) but technical and labour-intensive difficulties limit its application [1]. Quicker and simpler assays of FF are needed, particularly to assess the renal hemodynamic dysfunction (hyper- or hypofiltration) and effects/mode of action of therapeutic interventions in chronic kidney disease (CKD). We assessed a novel magnetic resonance imaging (MRI) technique to measure FF in patients with diabetic kidney disease (DKD) and healthy controls (HC) [2]. Method This cross-sectional sub-study included 32 DKD subjects with measured GFR (mGFR) ≤ 60 ml/ min/1.73 m2 and stratified into the following GFR stages as per the Kidney Disease Improving Global Outcomes (KDIGO) classification: stage G3a (mGFR 45-59 ml/ min/1.73 m2, n = 3), G3b (mGFR 30-44 ml/ min/1.73 m2, n = 8), G4 (mGFR 15-29 ml/ min/1.73 m2, n = 15), G5 (<15 ml/ min/1.73 m2, n = 6), and 18 age-, gender-matched HC with mGFR ≥ 60 ml/min/1.73 m2. All subjects were 18-79 years old. mGFR was assessed using iohexol clearance. Renal blood flow (RBF) (ml/min) was measured by a 5-minute add-on phase contrast MRI of the renal artery of each kidney and then summed together. RBF was corrected for Body Surface Area. RPF and FF were calculated as below: ${\rm{RPF }} = {\rm{ RBF}} \times \ ( {1\ -{\rm{ Hematocrit}}} )$ ${\rm{FF}} = {\rm{mGFR}}/{\rm{RPF}}$ Results RBF and mGFR were highly correlated (R2 = 0.70, Fig. 1). FF was 17.1% for HC and decreased with increasing degrees of renal impairment (Fig. 2). While the difference between HC and G3a DKD group was not significant, there was highly significant difference between HC and all other DKD groups (p < 0.001). The standard deviation in the G3a group was relatively large with only 3 subjects in this group. Conclusion The phase contrast MRI scan can provide a quick and simple measurement of glomerular hemodynamics and therewith further insights into the pathophysiology of DKD and its progression. Given the limitations of the existing method for assessing renal plasma flow, this MRI method can facilitate the inclusion of filtration fraction in DKD clinical trials. Further, the described method could be used to identify hyperfiltration, a compensatory mechanism that can influence results in clinical trials of DKD.

#2584 Mapping Progression of DKD in ReninAAV UNx db/db mice utilizing time-series RNA sequencing

Abstract Background and Aims The Renin adeno-associated virus (AAV) uninephrectomized (UNx) db/db mouse model of diabetic kidney disease (DKD) recapitulates hallmarks of DKD with hypertension, including albuminuria and glomerulosclerosis. Despite previous characterization of the model, gaps persist in our understanding regarding temporal patterns of gene expression and pathophysiology in the glomeruli. This longitudinal study characterizes isolated glomeruli from ReninAAV UNx db/db mice during progression of DKD with hypertension. Method Female db/db (BKS.Cg-Dock7m +/+ Leprdb/J) received a single i.v. dose of LacZAAV (control) or ReninAAV. Untreated db/m mice (BKS.Cg-Dock7m +/+ Leprdb/J) served as healthy controls. One week after AAV injection, ReninAAV mice underwent UNx, recovered for three weeks, and were subsequently randomized and stratified into 4 groups according to fed blood glucose and body weight. ReninAAV UNx mice were terminated at 4, 8, 12 and 16 weeks (w4-w16) after UNx. Control groups were terminated at 16 weeks. Endpoints included urine and plasma biochemistry, kidney histology (i.e. Collagen 1a1 and Glomerulosclerosis) and RNA sequencing of glomeruli isolated by laser capture microdissection. Results ReninAAV UNx db/db mice showed progressive kidney fibrosis (Col1a1%-area) and albuminuria (uACR) compared to LacZAAV db/db and db/m mice across all timepoints investigated. Furthermore, a significant increase in glomerulosclerosis was observed from w12 and onwards compared to LacZAAV and db/m mice. When compared to LacZAAV mice, more than 1,700 glomerular differentially regulated genes and more than 250 uniquely regulated genes were found at each timepoint, including markers of fibrosis, inflammation and glomerular injury. Several glomerular drug targets exhibited time-specific regulated in ReninAAV UNx db/db mice (e.g. Slc5a2, Egfr, Agtr1a). Regulated genes were segmented into nine clusters with distinct temporal patterns. Among these, a continuous increase in expression of genes associated with extracellular matrix (ECM), small molecule transport and temporal stimulation of metabolic pathways. Finally, a correlation analysis revealed strong associations between ECM and ECM-related pathways vs. glomerulosclerosis and albuminuria. Conclusion The ReninAAV UNx db/db mouse model of hypertensive DKD demonstrates a progressive increase in fibrosis and albuminuria paralleled by dynamic changes in glomerular gene expression signatures. Notably, the identification of temporal patterns of gene expression and pathway regulation provides novel insights into DKD pathophysiology and progression. This underscores the ReninAAV UNx db/db mouse as an applicable model of human DKD in preclinical target and drug discovery.

The role of long non-coding RNAs in the development of diabetic kidney disease and the involved clinical application.

Diabetic kidney disease (DKD), one of the common microvascular complications of diabetes, is increasing in prevalence worldwide and can lead to End-stage renal disease. However, there are still gaps in our understanding of the pathophysiology of DKD, and both current clinical diagnostic methods and treatment strategies have drawbacks. According to recent research, long non-coding RNAs (lncRNAs) are intimately linked to the developmental process of DKD and could be viable targets for clinical diagnostic decisions and therapeutic interventions. Here, we review recent insights gained into lncRNAs in pathological changes of DKD such as mesangial expansion, podocyte injury, renal tubular injury, and interstitial fibrosis. We also discuss the clinical applications of DKD-associated lncRNAs as diagnostic biomarkers and therapeutic targets, as well as their limitations and challenges, to provide new methods for the prevention, diagnosis, and treatment of DKD.

Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels.

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Therefore, efforts to understand DKD pathophysiology and prevent its development at the early phase are highly warranted. Here, we analyzed kidneys from healthy mice, diabetic mice, and diabetic mice treated with the sodium-glucose cotransporter 2 inhibitor dapagliflozin using ATAC and RNA sequencing. The findings were verified at the protein levels and in cultured cells. Our combined method of ATAC and RNA sequencing revealed Csf2rb, Btla, and Isg15 as the key candidate genes associated with hyperglycemia, azotemia, and albuminuria. Their protein levels were altered together with multiple other inflammatory cytokines in the diabetic kidney, which was alleviated by dapagliflozin treatment. Cell culture of immortalized renal tubular cells and macrophages unraveled that dapagliflozin could directly effect on these cells in vitro as an anti-inflammatory agent independent of glucose concentrations. We further proved that dapagliflozin attenuated ischemia/reperfusion-induced chronic kidney injury and renal inflammation in mice. Overall, our data emphasize the importance of inflammatory factors to the pathogenesis of DKD, and provide valuable mechanistic insights into the renoprotective role of dapagliflozin.

Diagnostic challenges of diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of both type 1 and type 2 diabetes and the most common cause of the end-stage renal disease (ESRD). It has been evidenced that targeted interventions at an early stage of DKD can efficiently prevent or delay the progression of kidney failure and improve patient outcomes. Therefore, regular screening for DKD has become one of the fundamental principles of diabetes care. Long-established biomarkers such as serum-creatinine-based estimates of glomerular filtration rate and albuminuria are currently the cornerstone of diagnosis and risk stratification in routine clinical practice. However, their immanent biological limitations and analytical variations may influence the clinical interpretation of the results. Recently proposed new predictive equations without the variable of race, together with the evidence on better accuracy of combined serum creatinine and cystatin C equations, and both race- and sex-free cystatin C-based equation, have enabled an improvement in the detection of DKD, but also require the harmonization of the recommended laboratory tests, wider availability of cystatin C testing and specific approach in various populations. Considering the complex pathophysiology of DKD, particularly in type 2 diabetes, a panel of biomarkers is needed to classify patients in terms of the rate of disease progression and/or response to specific interventions. With a personalized approach to diagnosis and treatment, in the future, it will be possible to respond to DKD better and enable improved outcomes for numerous patients worldwide.

Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease.

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.

#4663 BLOOD AND URINARY CYTOKINE PROFILES AND CLINICAL OUTCOME IN PRIMARY MEMBRANOUS NEPHROPATHY AND DIABETIC KIDNEY DISEASES

Abstract Background and Aims Primary membranous nephropathy (MN) is an autoimmune, immune complex-mediated primary glomerulopathy causing podocyte injury and nephrotic syndrome. The results of therapy may be suboptimal and biomarkers are needed that predict the need for immune suppression and the response to different immunosuppression regimens. Diabetic kidney disease (DKD) is the most common cause of kidney failure. It is characterized by non-immune podocyte injury that may lead to nephrotic syndrome. We evaluated the circulating and urine cytokine pattern and pathophysiologic difference between both conditions. For MN, we further aimed at identifying the biomarkers of immunosuppressive treatment response. Method 192 MN data-points from the STARMEN trial and 92 DKD from the biobank of IIS-FJD-UAM were included. We analyzed the blood and urine samples by HISCL (Sysmex Inc. Kobe, Japan), a chemiluminescence immunoassay that can afford a high-throughput multiplex cytokine analysis. Sixteen biomarkers were measured and evaluated for the correlation with the clinical outcome (eGFR, uPCR, 24-hour proteinuria). Also, the biomarkers’ concentration at baseline was compared with the treatment response during 6-9 months and the disease status after treatment until 24 months. The treatments evaluated STARMEN were Tacrolimus-Rituximab (TacRt) and alternating therapy with corticosteroids-cyclophosphamide. Box plot and Mann Whitney U test were used to assess subgroup differences and Spearman's rank correlation to assess correlation between variables. Results Median age, baseline eGFR and proteinuria for the MN and DKD cohorts were 53 and 66 years, 74 and 52 ml/min/1.73 m2, and 8.8 and 0.2 g/24h, respectively. Five cytokine markers in blood and 5 in urine from MN and 2 in blood and 2 in urine from DKD showed a significant correlation with proteinuria (Table). Circulating TNFa had been previously related to both MN and DKD pathophysiology and we confirmed its correlation with clinical outcomes in both. CCL20 is one of blood biomarkers correlated with anti-PLA2R (rS = 0.151, p = 0.036) and proteinuria in MN but not DKD. We identified a baseline urinary Protein A whose concentration differed between responders and non-responders to TacRt. Conclusion MN and DKD displayed characteristic cytokine patterns. Protein A is related to the progression of chronic inflammation and B cells. Its presence in urine and the differences between TacRt responders and non-responders suggest that high inflammatory progression activities may offset the treatment response. In conclusion, protein A could be the potential prognostic marker of TacRt response. However, additional investigation is needed to confirm and evaluate the possible application to other glomerular diseases.

Irisin Ameliorates Renal Tubulointerstitial Fibrosis by Regulating the Smad4/β-Catenin Pathway in Diabetic Mice.

The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. The purpose of this article is to examine irisin's function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-β1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and β-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/β-catenin signaling pathway. The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/β-catenin pathway.

DNA methylation enzymes in the kidneys of male and female BTBR ob/ob mice.

Diabetic kidney disease (DKD) is the leading cause of the end-stage renal disease. Recent studies have shown that epigenetic modifications contribute to alterations in gene expression and the development of DKD. This study aimed to show an expression profile of key DNA (de)methylation enzymes (DNMT, TET proteins) and their differences between sexes under obesity and diabetic condition. Male and female black and tan brachyury (BTBR) ob/ob mice and their corresponding wild-type littermates (BTBR WT) were studied until 16 weeks of age. Metabolic parameters, kidney morphophysiology and the expression of fibrotic markers and epigenetic enzymes were studied in whole kidney tissue or specifically in the glomerulus. The results showed sexual dimorphism in the development of metabolic disease and in kidney morphophysiology. Female mice have a different profile of DNMTs expression in both WT and obese/diabetic condition. Furthermore, metabolic condition negatively modulated the glomerular expression of TET1 and TET3 only in females. To our knowledge, this is the first study that shows a kidney profile of the expression of key (de)methylation enzymes, DNMTs and TETs, in the BTBR ob/ob experimental model of DKD and its association with sex. The knowledge of this epigenetic profile may help future research to understand the pathophysiology of DKD in males and females.

Antagonistes du récepteur minéralocorticoïde

Diabetic kidney disease (DKD) and its associated cardiovascular morbidity represent a major complication in diabetic patients. Over the past two decades, several experimental studies have shown benefits of mineralocorticoid receptor (MR) antagonists on the cardiorenal outcomes in animal models of non-diabetic or diabetic kidney diseases. Here, we summarize the role of MR activation in promoting inflammatory and fibrotic mechanisms that contribute to DKD pathophysiology. We also review the key findings of two recent large clinical trials FIDELIO-DKD and FIGARO-DKD which showed for the first time a major benefit of the non-steroidal MR antagonist, finerenone, on renal and cardiac specific outcomes across the spectrum of DKD severity. We finally discuss the place of finerenone compared to other DKD therapeutic approaches.

SGLT2 Inhibitor-Dapagliflozin Attenuates Diabetes-Induced Renal Injury by Regulating Inflammation through a CYP4A/20-HETE Signaling Mechanism.

Diabetic kidney disease (DKD) is a serious complication of diabetes, affecting millions of people worldwide. Inflammation and oxidative stress are key contributors to the development and progression of DKD, making them potential targets for therapeutic interventions. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising class of drugs, with evidence demonstrating that they can improve renal outcomes in people with diabetes. However, the exact mechanism by which SGLT2i exert their renoprotective effects is not yet fully understood. This study demonstrates that dapagliflozin treatment attenuates renal injury observed in type 2 diabetic mice. This is evidenced by the reduction in renal hypertrophy and proteinuria. Furthermore, dapagliflozin decreases tubulointerstitial fibrosis and glomerulosclerosis by mitigating the generation of reactive oxygen species and inflammation, which are activated through the production of CYP4A-induced 20-HETE. Our findings provide insights onto a novel mechanistic pathway by which SGLT2i exerts their renoprotective effects. Overall, and to our knowledge, the study provides critical insights into the pathophysiology of DKD and represents an important step towards improving outcomes for people with this devastating condition.

Urinary microRNA in Diabetic Kidney Disease: A Literature Review.

Diabetic kidney disease is the most common primary disease of end-stage kidney disease globally; however, a sensitive and accurate biomarker to predict this disease remains awaited. microRNAs are endogenous single-stranded noncoding RNAs that have intervened in different post-transcriptional regulations of various cellular biological functions. Previous literatures have reported its potential role in the pathophysiology of diabetic kidney disease, including regulation of Transforming Growth Factor-β1-mediated fibrosis, extracellular matrix and cell adhesion proteins, cellular hypertrophy, growth factor, cytokine production, and redox system activation. Urinary microRNAs have emerged as a novel, non-invasive liquid biopsy for disease diagnosis. In this review, we describe the available experimental and clinical evidence of urinary microRNA in the context of diabetic kidney disease and discuss the future application of microRNA in routine practice.

Sex differences in risk factors for end-stage kidney disease and death in type 2 diabetes: A retrospective cohort study.

This study investigated the sex differences in the risk of end-stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. During a median follow-up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02-1.75; p=.034) and death (HR 1.64; 95% CI 1.24-2.16; p=.001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo- and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

Gut microbiota and its metabolites - molecular mechanisms and management strategies in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus and is also one of the serious risk factors in cardiovascular events, end-stage renal disease, and mortality. DKD is associated with the diversified, compositional, and functional alterations of gut microbiota. The interaction between gut microbiota and host is mainly achieved through metabolites, which are small molecules produced by microbial metabolism from exogenous dietary substrates and endogenous host compounds. The gut microbiota plays a critical role in the pathogenesis of DKD by producing multitudinous metabolites. Nevertheless, detailed mechanisms of gut microbiota and its metabolites involved in the occurrence and development of DKD have not been completely elucidated. This review summarizes the specific classes of gut microbiota-derived metabolites, aims to explore the molecular mechanisms of gut microbiota in DKD pathophysiology and progression, recognizes biomarkers for the screening, diagnosis, and prognosis of DKD, as well as provides novel therapeutic strategies for DKD.

Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis

BackgroundThe pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD.MethodsWe conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups—normal, DM without CKD, CKD without DM, and DKD—and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins.ResultsWe identified three novel SNPs [rs3128852 (P = 8.21×10−25), rs117744700 (P = 8.28×10−10), and rs28366355 (P = 2.04×10−8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues.ConclusionsWe successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

Precision Medicine in Diabetic Kidney Disease: A Narrative Review Framed by Lived Experience

Purpose of review: Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) for which many treatments exist that have been shown to prevent CKD progression and kidney failure. However, DKD is a complex and heterogeneous etiology of CKD with a spectrum of phenotypes and disease trajectories. In this narrative review, we discuss precision medicine approaches to DKD, including genomics, metabolomics, proteomics, and their potential role in the management of diabetes mellitus and DKD. A patient and caregivers of patients with lived experience with CKD were involved in this review. Sources of information: Original research articles were identified from MEDLINE and Google Scholar using the search terms “diabetes,” “diabetic kidney disease,” “diabetic nephropathy,” “chronic kidney disease,” “kidney failure,” “dialysis,” “nephrology,” “genomics,” “metabolomics,” and “proteomics.” Methods: A focused review and critical appraisal of existing literature regarding the precision medicine approaches to the diagnosis, prognosis, and treatment of diabetes and DKD framed by a patient partner’s/caregiver’s lived experience. Key findings: Distinguishing diabetic nephropathy from CKD due to other types of DKD and non-DKD is challenging and typically requires a kidney biopsy for a diagnosis. Biomarkers have been identified to assist with the prediction of the onset and progression of DKD, but they have yet to be incorporated and evaluated relative to clinical standard of care CKD and kidney failure risk prediction tools. Genomics has identified multiple causal genetic variants for neonatal diabetes mellitus and monogenic diabetes of the young that can be used for diagnostic purposes and to specify antiglycemic therapy. Genome-wide-associated studies have identified genes implicated in DKD pathophysiology in the setting of type 1 and 2 diabetes but their translational benefits are lagging beyond polygenetic risk scores. Metabolomics and proteomics have been shown to improve diagnostic accuracy in DKD, have been used to identify novel pathways involved in DKD pathogenesis, and can be used to improve the prediction of CKD progression and kidney failure as well as predict response to DKD therapy. Limitations: There are a limited number of large, high-quality prospective observational studies and no randomized controlled trials that support the use of precision medicine based approaches to improve clinical outcomes in adults with or at risk of diabetes and DKD. It is unclear which patients may benefit from the clinical use of genomics, metabolomics and proteomics along the spectrum of DKD trajectory. Implications: Additional research is needed to evaluate the role of the use of precision medicine for DKD management, including diagnosis, differentiation of diabetic nephropathy from other etiologies of DKD and CKD, short-term and long-term risk prognostication kidney outcomes, and the prediction of response to and safety of disease-modifying therapies.

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. Considering DKD is the main cause of end-stage renal disease (ESRD) in developed countries, extensive research is currently investigating the matrix of DKD pathophysiology. Hyperglycemia, inflammation and oxidative stress (OS) are the main mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-β, NF-κB, MCP-1, VCAM-1, ICAM-1) and the activation of diverse pathways (e.g., PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state with impairment of the antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations in the renal filtration unit. Hitherto, a wide spectrum of pre-clinical and clinical studies shows the beneficial use of NRF2-inducing strategies, such as NRF2 activators (e.g., Bardoxolone methyl, Curcumin, Sulforaphane and their analogues), and other natural compounds with antioxidant properties in DKD treatment. However, limitations regarding the lack of larger clinical trials, solubility or delivery hamper their implementation for clinical use. Therefore, in this review, we will discuss DKD mechanisms, especially oxidative stress (OS) and NRF2/KEAP1/ARE involvement, while highlighting the potential of therapeutic approaches that target DKD via OS.

Pioglitazone in diabetic kidney disease: forgotten but not gone.

Diabetic kidney disease (DKD) is described in approximately 20–40% of all diabetic patients and is associated with significant cardiovascular and all-cause mortality. The involvement of multiple metabolic, haemodynamic, inflammatory, and tubular pathways in the pathophysiology of DKD generates the need for multitargeted treatment approaches to improve its development at all levels and delay or even reverse its progression. Thiazolidinediones are potent exogenous agonists of PPAR-γ, which augment the effects of insulin on its cellular targets, mainly at the level of adipose tissue. Pioglitazone, currently the main thiazolidinedione in clinical practice, has achieved significant improvements of albuminuria in patients with type 2 diabetes. It can also interfere with most cellular pathways involved in the development and evolution of DKD. This paper explores the pathophysiological mechanisms governing its possible nephroprotective activity during a diabetic state. It also discusses its future role to ameliorate the global burden of DKD.

ZnT8 Exerts Anti-apoptosis of Kidney Tubular Epithelial Cell in Diabetic Kidney Disease Through TNFAIP3-NF-κB Signal Pathways.

Apoptosis of kidney tubular epithelial cells contributes to diabetic kidney disease (DKD) pathophysiology, but the mechanisms are not fully understood. Zinc transporter protein member 8 (ZnT8, SLC30A8) is a susceptive gene in diabetes. Here, we aim to investigate whether ZnT8 has effects on pathophysiology of DKD. The animal groups include control, ZnT8KO mice, STZ-induced, and ZnT8-KO-STZ. STZ-induced DKD was performed in male C57BL/6J mice and in ZnT8-KO mice. High glucose (HG)-induced apoptosis in a normal rat kidney tubular epithelial cell line (NRK-52E cells) was performed in vitro. Transfection of hZnT8-EGFP or TNFAIP3 siRNA was done in NRK-52E cells. Flow cytometry with Annexin V-FITC/PI double staining and TUNEL analysis was performed for the detection of apoptosis. Gene expression at mRNA and protein levels was examined with real-time RT-PCR and Western blot. Urine albumin to creatinine ratio, proinflammatory cytokines, and apoptosis were enhanced in kidneys of STZ and ZnT8-KO-STZ mice compared to control or ZnT8-KO mice. ZnT8 overexpression after hZnT8-EGFP transfection decreased HG-stimulated inflammatory activity and apoptosis in NRK-52E cells. Furthermore, treatment with ZnSO4 blunted HG-induced apoptosis and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3). Also, ZnT8 over-expression after hZnT8-EGFP transfection significantly ameliorates HG-induced NF-κB-dependent transcriptional activity and apoptotic protein expressions in NRK-52E cells, but the inhibitory effect of ZnT8 was significantly abolished with TNFAIP3 siRNA. Our study provides evidence that ZnT8 has protective effects against apoptosis of renal tubular epithelial cells through induction of TNFAIP3 and subsequent suppression of the NF-κB pathway.

Impact of SGLT2 inhibitors on the kidney in people with type 2 diabetes and severely increased albuminuria

ABSTRACT Introduction Diabetes is the most common cause of end-stage kidney disease. Therapies such as sodium-glucose co-transporter-2 inhibitors have been identified over the last decade as effective oral hypoglycemic agents that also confer additional cardio and kidney protection. Knowledge of their mechanism of action and impact on patients with diabetes and albuminuria is vital in galvanizing prescriber confidence and increasing clinical uptake. Areas covered This manuscript discusses the pathophysiology of diabetic kidney disease, patho-physiological mechanisms for sodium-glucose co-transporter-2 inhibitors, and their impact on patients with type 2 diabetes mellitus and albuminuric kidney disease. Expert opinion Sodium-glucose co-transporter-2 inhibitors reduce albuminuria with consequent benefits on cardiovascular and kidney outcomes in patients with diabetes and severe albuminuria. While they have been incorporated into guidelines, the uptake of these agents into clinical practice has been slow. Increasing the uptake of these agents into clinical practice is necessary to improve outcomes for the large number of patients with diabetic kidney disease globally. P LAIN LANGUAGE SUMMARY People with type 2 diabetes and severe urinary protein loss are at high risk of progression to kidney failure requiring dialysis or transplantation. Preventing or slowing down loss of kidney function is crucial to preventing kidney failure. This review will discuss how diabetic kidney disease occurs, how a new family of glucose-lowering agents, the sodium-glucose co-transporter-2 inhibitors, work and how they affect people with type 2 diabetes mellitus who also have protein leaking from their kidneys. It will also detail the current data that underpins the guideline recommendations for use of these agents in the management of patients with and without diabetes.