ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in <i>Nos3</i>-Deficient Mice

Tesch, Gregory H; Ma, Frank; Han, Yingjie; Liles, John T.; Breckenridge, David G.; Nikolic-Paterson, David J.

doi:10.2337/db15-0384

Cited by 82 publications

(59 citation statements)

References 42 publications

(54 reference statements)

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“…Our study has identified a strategy for achieving similar levels of diabetes in male and female Nos3‐/‐ mice. As previously shown (Tesch et al ), male mice develop significant diabetes at week 1 after the fifth injection of STZ (55 mg/kg/day), which subsequently reaches a stable plateau at week 3. In comparison, female mice are more resistant to developing diabetes, but will achieve a similar level of diabetes as males from week 3 if they are given an extra (sixth) injection of STZ at 1 week after the fifth injection.…”

Section: Discussion/conclusionsupporting

confidence: 70%

“…Real‐time RT‐PCR was performed on a StepOne machine (Applied Biosystems, Mulgrave, VIC, Australia) with thermal cycling conditions of 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 sec and 60°C for 1 min. Primers and FAM‐labeled MGB probes for detection of CD68, TNF‐ α , CCL2, KIM‐1, TGF‐ β 1, fibronectin, and collagen I and IV have been described previously (Tesch et al ). Primers and VIC‐labeled probes for 18S ribosomal RNA were purchased from Applied Biosystems.…”

Section: Methodsmentioning

confidence: 99%

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Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Tian

Tesch

2019

Physiol Rep

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Clinical studies indicate that sex differences exist in susceptibility for developing diabetic kidney disease (DKD), supporting the need to examine both sexes in animal studies of DKD. Streptozotocin (STZ) is commonly used in male mice to induce diabetes and DKD. However, females are not normally included because their sex hormones partially protect them from STZ‐induced islet injury and consequent diabetes. To address this issue, we identified a strategy to induce comparable diabetes in male and female mice using STZ and determined whether both sexes develop equivalent renal injury. Male and female mice lacking the gene for endothelial nitric oxide synthase (Nos3‐/‐) were made diabetic with five or six low‐dose STZ injections, respectively. Groups of male and female mice with equivalent hyperglycemia at week 3 after STZ were assessed for DKD at week 8. STZ‐treated male and female Nos3‐/‐ mice maintained comparable hyperglycemia between weeks 3 and 8 had an equivalent increase in HbA1c levels and comparable hypertension. Urine albumin/creatinine levels were elevated eightfold in mice of both sexes at week 8, accompanied by an equivalent loss of podocytes. In diabetic males and females, plasma cystatin C levels and glomerular collagen deposition were similarly increased. Kidney mRNA levels of proinflammatory and profibrotic markers and kidney injury molecule‐1 (KIM‐1) were equally elevated in males and females, indicating comparable kidney injury. This study shows that equivalent diabetes induces a comparable onset of DKD in male and female Nos3‐/‐ mice, demonstrating that it is possible to include males and females together in studies of DKD.

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Section: Discussion/conclusionsupporting

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Tian

Tesch

2019

Physiol Rep

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“…ASK1 signals through a cascade of downstream kinases including p38 and c-Jun N-terminal kinase (JNK), leading to target gene expression including inflammatory cytokines 131132 . A preliminary report suggests that ASK1 inhibition substantially improves glomerulosclerosis in a diabetic animal model 133 . Gilead Sciences has initiated a 300 patient phase 2 program to test the efficacy of the selective ASK1 inhibitor GS-4997 in diabetic nephropathy.…”

Section: Anti-inflammatory Therapymentioning

confidence: 99%

The next generation of therapeutics for chronic kidney disease

Breyer

Suszták

2016

Nat Rev Drug Discov

227

183

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Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for the disease, with current treatment strategies relying on blood pressure control through blockade of the renin angiotensin system and glycemic control. Such approaches only delay end stage kidney disease development, and can be associated with significant side effects. Recent identification of several novel mechanisms contributing to CKD development - including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation – has revealed new potential therapeutic approaches for CKD. This review will assess emerging strategies and agents for CKD treatment, highlighting associated challenges in their clinical development.

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“…Several issues need to be clarified, however. ASK1 inhibition did not improve podocyte loss and albuminuria in experimental diabetic CKD, suggesting that this kinase is not central for glomerular injury (73). Furthermore, the impact of ASK1 inhibitors in nondiabetic CKD is unknown.…”

Section: Targeting Redox Regulation In the Pathogenesis Of Nafld And Ckdmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice

Cited by 82 publications

References 42 publications

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

The next generation of therapeutics for chronic kidney disease

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

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