title: Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System.
abstract: Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited β-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders.
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Mo
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: liuy@upmc.edu.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D006977:Hypertension, Renal / Q000188:drug therapy; D007668:Kidney / Q000473:pathology*; D000090265:Klotho Proteins; D008297:Male; D008815:Mice, Inbred Strains; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D005966:Glucuronidase; D000090265:Klotho Proteins