Klotho is a recently-discovered anti-aging gene. Genetic mutation of klotho results in multiple premature aging phenotypes. In contrast, mice that overexpress klotho enjoy an extended lifespan. Thus, klotho may be an aging-suppressor gene that can delay aging when over expressed and accelerate aging when disrupted. Cardiovascular disease is associated with aging. For instance, the prevalence of hypertension increases with age while the level of the circulating klotho declines with age. It is not known, however, if klotho is involved in the maintenance of blood pressure. Whether klotho gene deficiency causes hypertension has never been determined. Klotho is predominately expressed in the renal distal convoluted tubule (DCT) epithelial cells although it is also found in a few of other types of cells or tissues. Kidney-specific knockout of klotho gene (KL-KO) was achieved using a cadherin promoter-Cre recombinase transgene and the loxP-flanked klotho gene. Our new exciting preliminary data showed that kidney-specific conditional KL-KO impaired renal Na excretion and vascular endothelial function and increased blood pressure (BP) significantly in mice. The level of the circulating klotho protein was decreased in spontaneous hypertensive rats (SHR). The objective of the proposed research is to determine if klotho plays a role in the maintenance of BP and if klotho deficiency is involved in the pathogenesis of hypertension. This objective will be achieved by pursuing three interrelated specific aims using a combination of several novel approaches including kidney-specific conditional gene knockout, in vivo DCT- and endothelial cell-specific gene delivery, and real-time monitoring of blood pressure (telemetry).
The specific aims are: (1) Determine if klotho plays a role in the maintenance of blood pressure by testing the effect of kidney-specific conditional KL-KO on Na excretion, endothelial function, and blood pressure. (2) Determine a novel role of klotho in the regulation of Na-Cl cotransporter (NCC) and Na, K-ATPase (ATPase) in the DCT cells in kidneys. (3) Determine the role of the circulating klotho in the development of spontaneous hypertension and vascular dysfunction by DCT-specific gene delivery of ADAM10, a disintegrin that cleaves and releases klotho from DCT cells. These studies will demonstrate, for the first time, important roles of klotho in the maintenance of blood pressure and in the pathogenesis of hypertension. The results will provide novel mechanism that klotho protects the cardiovascular system. Completion of the project may reveal new insights into therapeutic strategies for hypertension and related cardiovascular disorders.

Public Health Relevance

Cardiovascular disease is associated with aging. For instance, the prevalence of hypertension increases with age. The purpose of the proposed research is to determine the role of klotho, a recently-discovered anti-aging gene, in the regulation of blood pressure and in the pathogenesis of spontaneous hypertension. The results will provide novel information that klotho protects the cardiovascular system. Completion of the project may offer a new therapeutic approach for hypertension and related cardiovascular disorders. The finding will benefit the US population which has a high prevalence of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102074-04
Application #
8622211
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2011-02-15
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$1,228,524
Indirect Cost
$395,071
Name
University of Oklahoma Health Sciences Center
Department
Physiology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Gao, Diansa; Zuo, Zhong; Tian, Jing et al. (2016) Activation of SIRT1 Attenuates Klotho Deficiency-Induced Arterial Stiffness and Hypertension by Enhancing AMP-Activated Protein Kinase Activity. Hypertension 68:1191-1199
Lin, Yi; Chen, Jianglei; Sun, Zhongjie (2016) Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase. Hypertension 67:564-73
Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang et al. (2016) Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity. Hypertension 68:1255-1263
Chen, Kai; Zhou, Xiaoli; Sun, Zhongjie (2015) Haplodeficiency of Klotho Gene Causes Arterial Stiffening via Upregulation of Scleraxis Expression and Induction of Autophagy. Hypertension 66:1006-13
Lin, Yi; Sun, Zhongjie (2015) Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes. Diabetes 64:4298-311
Lin, Yi; Sun, Zhongjie (2015) In vivo pancreatic β-cell-specific expression of antiaging gene Klotho: a novel approach for preserving β-cells in type 2 diabetes. Diabetes 64:1444-58
Sun, Zhongjie (2015) Aging, arterial stiffness, and hypertension. Hypertension 65:252-6
Zhou, Xiaoli; Chen, Kai; Lei, Han et al. (2015) Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol 26:121-32
Wang, Yuhong; Sun, Zhongjie (2014) Antiaging gene Klotho regulates endothelin-1 levels and endothelin receptor subtype B expression in kidneys of spontaneously hypertensive rats. J Hypertens 32:1629-36; discussion 1636
Crosswhite, Patrick; Chen, Kai; Sun, Zhongjie (2014) AAV delivery of tumor necrosis factor-α short hairpin RNA attenuates cold-induced pulmonary hypertension and pulmonary arterial remodeling. Hypertension 64:1141-50

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