# Klotho and chronic kidney disease

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $520,846

## Abstract

Project Summary
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.
.

## Key facts

- **NIH application ID:** 10133460
- **Project number:** 5R01DK100605-07
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Chou-Long Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,846
- **Award type:** 5
- **Project period:** 2014-09-20 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133460

## Citation

> US National Institutes of Health, RePORTER application 10133460, Klotho and chronic kidney disease (5R01DK100605-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133460. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*