Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist, Lina; Friederich‐Persson, Malou; Fasching, Angelica; Liss, Per; Shoji, Keisuke; Nangaku, Masaomi; Hansell, Peter; Palm, Fredrik

doi:10.1681/asn.2013090990

Cited by 176 publications

(154 citation statements)

References 43 publications

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“…A role for HIF-1 in the pathogenesis of renal fibrosis including that of diabetic nephropathy has been shown by several groups (18,38,39), although others have recently suggested that HIF activation may protect against diabetic nephropathy (40). In this latter study, diabetic rats were treated for 4 weeks with cobalt chloride, a relatively nonspecific activator of HIF.…”

Section: Discussionmentioning

confidence: 89%

High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells

Uttarwar

Gao

et al. 2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 89%

High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells

Uttarwar

Gao

et al. 2015

Journal of Biological Chemistry

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“…This concept has been supported by numerous studies using several animal models of CKD [86][87][88]. Recently, Palm and colleagues [89] demonstrated that the administration of cobalt ameliorated kidney damage in streptozotocin-induced diabetic rats, which was accompanied by increased oxygen tension in the kidney. However, these studies have several limitations.…”

Section: Hif Stabilization As a Treatment Of Ckdmentioning

confidence: 90%

Hypoxia and hypoxia-inducible factors in chronic kidney disease

Tanaka

Nangaku

2016

Ren Replace Ther

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It is generally accepted that renal hypoxia plays an important role in the progression of chronic kidney disease (CKD). This review focuses on renal hypoxia and hypoxia-inducible factor (HIF), a master regulator of cellular adaptation to hypoxia, during CKD progression. The kidney, which is physiologically hypoxic, is exposed to increased levels of hypoxia in CKD; insufficient oxygenation in the tubulointerstitium triggers injury and accelerates the deterioration of renal function, culminating in end-stage kidney disease (ESKD). HIF accumulates during specific stages of pathological progression; however, adaptation to hypoxia usually fails. In such cases, decreased vascular endothelial growth factor expression and upregulated antiangiogenic factors result in sustained capillary rarefaction. In addition, oxygen consumption in tubules is primarily increased by enhanced oxidative stress, and the transcriptional activity of HIF becomes suboptimal, which is partly mediated by methylglyoxal in diabetic kidney disease and by indoxyl sulfate, a representative uremic toxin, in advanced CKD. Oxygen-dependent canonical regulators of HIF involve prolyl hydroxylase domain-containing protein (PHD) and factor inhibiting HIF-1 (FIH-1), whereas recent studies have revealed noncanonical and oxygen-independent HIF regulation in the kidney. As a consequence, HIF accumulation usually fails to protect the kidney against hypoxia, which is likely to accelerate progression to ESKD, via several maladaptation mechanisms. The precise roles of HIF and its regulation in CKD warrant further investigation in light of promising data demonstrating that HIF stabilization by PHD inhibitors may be a new therapeutic approach for CKD.

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“…Several issues remain, however. In some studies, HIF-1a activation protected against kidney injury (66), suggesting that HIF-1a may not be the sole, or the best, therapeutic target for reversing cellular effects of hypoxia in CKD.…”

Section: Role Of Cellular Energy Oxygen and Nutrient Sensorsmentioning

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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Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Cited by 176 publications

References 43 publications

High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells

High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells

Hypoxia and hypoxia-inducible factors in chronic kidney disease

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

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