title: Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease.
abstract: Hypertensive chronic kidney disease is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. However, early events initiating the progression to hypertensive chronic kidney disease are poorly understood. We hypothesized that elevated endothelial hypoxia-inducible factor-1α (HIF-1α) is a common early insult triggering initial glomerular injury leading to hypertensive chronic kidney disease. To test our hypothesis, we used an angiotensin II infusion model of hypertensive chronic kidney disease to determine the specific cell type and mechanisms responsible for elevation of HIF-1α and its role in the progression of hypertensive chronic kidney disease. Genetic studies coupled with reverse transcription polymerase chain reaction profiling revealed that elevated endothelial HIF-1α is essential to initiate glomerular injury and progression to renal fibrosis by the transcriptional activation of genes encoding multiple vasoactive proteins. Mechanistically, we found that endothelial HIF-1α gene expression was induced by angiotensin II in a nuclear factor-κB-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1α and Nf-κb genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1α gene expression in endothelial cells is detrimental to induce kidney injury, hypertension, and disease progression. Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive chronic kidney disease.
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Weiru
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.).
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: From the Departments of Nephrology (R.L., L.T., Y.X.) and Urology (C.Z.), Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China; Departments of Biochemistry and Molecular Biology (R.L., W.Z., C.Z., Y.Z., H.W., J.J., R.E.K., Y.X.) and Internal Medicine (W.Z.), University of Texas Medical School at Houston; Program in Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, University of Texas, Houston (J.J., W.Z., R.E.K., Y.X.); and Department of Anesthesiology, University of Colorado-Medical School, Denver (A.G., H.K.E.). yang.xia@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D025461:Feedback, Physiological; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D034741:RNA, Small Interfering / Q000494:pharmacology; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D000099152:Cadherin 5
chemical_list: D000804:Angiotensin II; D015703:Antigens, CD; D015820:Cadherins; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000099152:Cadherin 5; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse
keywords: angiotensin II; hypertension; hypoxia-inducible factor 1, alpha; renal insufficiency, chronic