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 (soluble klotho; sKL) 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 sKL protects the heart by inhibiting TRPC6-mediated abnormal Ca2+ signaling and that membrane lipid rafts are receptors for sKL. Our over-arching hypothesis is that sKL binds lipid rafts to exert cardiac protection and that sKL deficiency is a cause of uremic cardiac hypertrophy. To support this hypothesis along with the long-term goal of developing potential treatment, we propose two aims.
Aim -1 will identify and develop potential sKL-mimetic that exerts organ protection by binding and targeting sialogangliosides and lipid rafts. We will produce recombinant sKL and sKL-mimetic proteins and examine their effects to bind sialoganglioside moiety in vitro and to protect organ in vivo.
Aim -2 will further elucidate the molecular mechanism for sKL regulation of TRPC6-mediated abnormal Ca2+ signaling. Supported by the preliminary data, we will test the hypothesis that TRPC6-containing vesicles are pre-docked to lipid rafts and that binding of cationic amino acids in the C-terminal region of TRPC6 to PIP3 (stimulated by PI3K) in the inner leaflet of raft membrane is important. Furthermore, we will examine molecular mechanism by which DAG stimulates TRPC6 vesicle exocytosis, thereby sKL inhibits TRPC6 function. We will use combined biochemical, electrophysiological, and imaging approaches. Our proposed studies in mice 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. .
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. .
| Dalton, George; An, Sung-Wan; Al-Juboori, Saif I et al. (2017) Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc Natl Acad Sci U S A 114:752-757 |
| Kim, Ji-Hee; Xie, Jian; Hwang, Kyu-Hee et al. (2017) Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes. J Am Soc Nephrol 28:140-151 |
| 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 |
| Cheng, C-J; Rodan, A R; Huang, C-L (2017) Emerging Targets of Diuretic Therapy. Clin Pharmacol Ther 102:420-435 |
| Mizuno, Masaki; Mitchell, Jere H; Crawford, Scott et al. (2016) High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats. Am J Physiol Regul Integr Comp Physiol 311:R39-48 |
| 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 |
