Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure. The condition can also lead to accelerated cardiovascular disease and macrovascular complications. Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease. Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor beta 1 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN. These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs. In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN.
Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. To prevent the development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. In this paper, the efficacy of fenugreek to restore the kidney function of diabetic rats via its antioxidant and anti-inflammatory activities has been studied. Novel data showing the efficacy of fenugreek to attenuate progression of diabetic nephropathy and production of interleukin-6 (IL-6) in rats compared with a diabetic untreated group were obtained. Rats were classified into five groups; control, diabetic untreated, and three diabetic groups treated with fenugreek, rosiglitazone, and metformin. Treatment with fenugreek has been continued for 12 weeks. Fenugreek was found to significantly reduce the high levels of glucose, urea, creatinine, sodium, potassium, and IL-6 in serum compared with the diabetic untreated group. In addition, levels of malondialdehyde and IL-6 in the kidney homogenate were significantly reduced as a result of the fenugreek treatment compared with the diabetic untreated group. Moreover, concentration of GSH and the activity of both superoxide dismutase and catalase were considerably increased in the diabetic treated groups compared with the diabetic untreated group. Furthermore, glomerular mesangial expansion was reduced in the treated animal groups. These findings suggest a therapeutic potential of fenugreek against diabetic nephropathy, explain its antioxidative/anti-inflammatory properties and provide a direction for future research.
Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally. Much research has been conducted in both basic science and clinical therapeutics, which has enhanced understanding of the pathophysiology of diabetic nephropathy and expanded the potential therapies available. This review will examine the current concepts of diabetic nephropathy management in the context of some of the basic science and pathophysiology aspects relevant to the approaches taken in novel, investigative treatment strategies.
In 2014, key studies in the field of diabetic nephropathy highlighted the importance of albuminuria as a predictor of cardiovascular risk and showed that the incidence of renal and cardiovascular complications is decreasing. Promising efficacy data were obtained with atrasentan, whereas a trial of bardoxolone methyl led to safety concerns.
Despite improvements in glycaemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway-further research into the potential nephroprotective effects of novel glucose-lowering agents is required.
AIMS: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS: SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION: SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.
Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC), leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic cytokine transforming growth factor beta (TGF beta 1; 0.5 ng/ml) in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGF beta 1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-kappa B) and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-kappa B suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGF beta increases SGLT2 expression through phosphorylated smad3.
OBJECTIVE-Despite the beneficial effects of resveratrol (RSV) on cardiovascular disease and life span, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of RSV in db/db mice, a model of type 2 diabetes. RESEARCH DESIGN AND METHODS-db/db mice were treated with RSV (0.3% mixed in chow) for 8 weeks. We measured urinary albumin excretion (UAE), histological changes (including mesangial expansion, fibronectin accumulation, and macrophage infiltration), oxidative stress markers (urinary excretion and mitochondrial content of 8-hydroxy-2'-deoxyguanosine [8-OHdG], nitrotyrosine expression), and manganese-superoxide dismutase (Mn-SOD) activity together with its tyrosine-nitrated modification and mitochondrial biogenesis in the kidney. Blood glucose, glycated hemoglobin, and plasma lipid profiles were also measured. The phosphorylation of 5'-AMP-activated kinase (AMPK) and expression of silent information regulator 1 (SIRT1) in the kidney were assessed by immunoblotting. RESULTS-RSV significantly reduced UAE and attenuated renal pathological changes in db/db mice. Mitochondrial oxidative stress and biogenesis were enhanced in db/db mice; however, Mn-SOD activity was reduced through increased tyrosine-nitrated modification. RSV ameliorated such alterations and partially improved blood glucose, glycated hemoglobin, and abnormal lipid profile in db/db mice. Activation of AMPK was decreased in the kidney of db/db mice compared with db/m mice. RSV neither modified AMPK activation nor SIRT1 expression in the kidney. CONCLUSIONS-RSV ameliorates renal injury and enhanced mitochondrial biogenesis with Mn-SOD dysfunction in the kidney of db/db mice, through improvement of oxidative stress via normalization of Mn-SOD function and glucose-lipid metabolism. RSV has antioxidative activities via AMPK/SIRT1-independent pathway. Diabetes 60:634-643, 2011