Chronic kidney disease (CKD) affects approximately 10% of the general population. The prevalence of cardiac hypertrophy is markedly increased in CKD patients, reaching as high as 90% in advanced stages of CKD. Cardiovascular disease is the main cause of death for CKD patients;among which cardiac hypertrophy is an important underlying cause. Risk factors for cardiac hypertrophy in CKD include CKD-specific risk factors as well as conventional risk factors (hypertension and volume expansion, etc). Several CKD-specific risk factors have been proposed but their roles remain inconclusive. Klotho is a membrane protein predominantly produced in the kidney. The extracellular domain of Klotho is released into the systemic circulation and functions as a soluble endocrine hormone. Serum levels of soluble Klotho are decreased in human CKD patients and in mouse models of CKD. We recently reported that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by downregulation of TRPC6 channels in the heart. Thus, we hypothesize that Klotho deficiency contributes to the pathogenesis of cardiac hypertrophy and heart failure in CKD.
Aim -1 will examine cardiac hypertrophy and heart failure in wild-type, Klotho-deficient, and Klotho-overexpressing mice rendered CKD by 5/6 nephrectomy. To support that Klotho deficiency contributes to uremic cardiomyopathy, we will further examine the molecular mechanism by which Klotho protects uremic cardiomyopathy, including inhibition of cardiac TRPC6 channels and/or antagonism of TGFb1 signaling upregulated in the uremic hearts.
Aim -2 will examine whether Klotho replacement protects against cardiac hypertrophy and failure in CKD. We will perform structure-activity analysis to identify the domain of Klotho that inhibits TRPC6 or antagonizes TGFb1 signaling first in isolated cardiomyocytes. To support the critical role of identified domain in cardioprotection in vivo, we will generate transgenic mice that express the domain and test for cardioprotection. Furthermore, we will generate purified specific recombinant Klotho domain protein and test its therapeutic role in reversing or preventing cardiac hypertrophy in 5/6 nephrectomized CKD mice. Our proposed studies in mice in the current application will provide important pre-clinical information that may lead to treatment of CKD-induced cardiomyopathy. Furthermore, upregulation of TRPC6 and abnormal Ca2+-calcineurin-NFAT signaling is critical for sustaining and amplifying pathological cardiac hypertrophy and remodeling from diverse causes. Klotho-based therapeutic strategies may be applicable to diverse cardiac diseases.

Public Health Relevance

Chronic kidney disease (CKD) is a public health epidemic that affects ~10% of the general population and increases cardiovascular mortality of affected patients. Our studies to investigate the mechanism of cardiac hypertrophy in CKD will provide important information that may lead to treatment of the condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100605-01A1
Application #
8752459
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2014-09-20
Project End
2018-07-31
Budget Start
2014-09-20
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wright, Jon D; An, Sung-Wan; Xie, Jian et al. (2017) Modeled structural basis for the recognition of ?2-3-sialyllactose by soluble Klotho. FASEB J 31:3574-3586
Dalton, George D; Xie, Jian; An, Sung-Wan et al. (2017) New Insights into the Mechanism of Action of Soluble Klotho. Front Endocrinol (Lausanne) 8:323
Wu, Yueh-Lin; Xie, Jian; An, Sung-Wan et al. (2017) Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho. Kidney Int 91:830-841
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Xie, Jian; Yoon, Joonho; An, Sung-Wan et al. (2015) Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate. J Am Soc Nephrol 26:1150-60