Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease

Luo, Renna; Zhang, Weiru; Zhao, Cheng; Zhang, Yujin; H, Wu; Jin, Jianping; Zhang, Wenzheng; Grenz, Almut; Eltzschig, Holger K.; Tao, Ling; Kellems, Rodney E.; Xia, Yang

doi:10.1161/hypertensionaha.115.05578

Cited by 60 publications

(64 citation statements)

References 42 publications

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“…Zhang et al [27] have reported that blocking HIF-1α could inhibit the activation of both inflammatory response and oxidative stress. It has also been reported that overexpression of HIF-1α promotes fibrosis and contributes to CKD [28]. Prolonged activation of HIF-1α in kidney could lead to further tissue destruction [29], all of which indicates the crucial role of HIF-1α in CKD, including FSGS.…”

Section: Discussionmentioning

confidence: 99%

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Liu¹,

2019

Nephron

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Background: Focal segmental glomerulosclerosis (FSGS) is a common histologic pattern of kidney injury, which may eventually lead to end-stage renal disease. Objectives: Salidroside (SAL, p-hydroxyphenyl-β-D-glucoside) is an active component isolated from Rhodiolarosea, which has various pharmacological properties including anti-inflammation and antioxidation. SAL may attenuate FSGS, but the underlying mechanism is not clear. Thus, in this study, we focus on the renoprotective role of SAL in FSGS using Adriamycin nephropathy (AN) mouse models. Methods: In C57 BL/6 mice, AN was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then they were organized into 6 groups for the animal experiments: AN + saline group; AN + SAL group (40 mg/kg); AN + LY294002 (a selective phosphatidylinositol 3-kinase [PI3K] inhibitors, 50 mg/kg) group; AN + SAL + LY294002 group; AN + YC-1 (a selective hypoxia-inducible factor-1α [HIF-1α] inhibitors, 50 mg/kg) group; and AN + SAL + YC-1 group. All of the drugs were given on the day of Adriamycin injection and continued for 6 weeks, and the drugs were given by intraperitoneally. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. Results: In FSGS mouse models, SAL treatment could ameliorate proteinuria, renal function, and markers of Nephrotic Syndrome inhibit alpha-smooth muscle actin and fibronectin expression and downregulates the expression of HIF-1α. Besides, the levels of PI3K and p-protein kinase B (Akt) in renal tissues were significantly decreased after SAL injection. Eventually, SAL treatment results reduced inflammatory cytokines and reactive oxygen species production. Conclusions: In summary, SAL ameliorates FSGS mainly by inhibiting the expression of HIF-1α through PI3K/Akt pathway, which might offer an array of hope for ameliorating FSGS.

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Section: Discussionmentioning

confidence: 99%

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Liu¹,

2019

Nephron

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“…6 Endothelial NF-κB activation may upregulate HIF-1α expression, which reciprocally amplifies NF-κB signaling and enhances angiotensin II-induced hypertensive kidney injury. 23 In quiescent ECs, the anti-inflammatory transcription factor Krüpple-like factor 2 limits NF-κB activation and HIF-1α accumulation. 24 However, disturbed flow downregulates endothelial Krüpple-like factor 2 expression and primes the endothelium for inflammatory activation by hyperlipidemia.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

et al. 2015

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Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1α is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1α in atherosclerosis is unclear. HIF-1α was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1α in atherosclerosis, deletion of the Hif1 a gene was induced in ECs from apolipoprotein E knockout mice (EC- Hif1a −/− ) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC- Hif1a −/− compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC- Hif1a −/− mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1α expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1α–induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein–stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1α expression in ECs by mildly oxidized low-density lipoprotein–derived unsaturated lysophosphatidic acid. Endothelial HIF-1α promoted atherosclerosis by triggering miR-19a–mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1α/miR-19a pathway may be a therapeutic option against atherosclerosis.

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“…Inappropriate HIF-1a activation following such stimuli as chronic intermittent hypoxia and cholesterol overload has been found to be involved in NASH pathogenesis (22,62), whereas chronic hypoxia has been implicated in renal injury in early diabetic and obesity-related CKD (63,64) (Fig. 2B).…”

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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Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease

Cited by 60 publications

References 42 publications

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Salidroside Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis by Inhibiting the Hypoxia-Inducible Factor-1α Expression Through Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

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

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