# Klotho and Phosphate in Chronic Kidney Disease: Pathogenesis and Therapeutics

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $364,500

## Abstract

PROJECT SUMMARY
Chronic kidney disease (CKD) has reached epidemic proportions globally. The single most important killer of
CKD patients is cardiovascular disease (CVD) consisting of cardiac hypertrophy and fibrosis, and vascular
calcification. More CKD patients die from CVD than reaching the need for dialysis. The treatment of traditional
cardiovascular risk factors have met with limited success and we are in dire need to treat CKD-related CVD.
Uremic cardiomyopathy is a complex metabolic disease with a panoply of underlying pathophysiologic factors.
Our laboratory has focused on contributing mineral factors common to CVD and CKD-Mineral Bone Disorders
(MBD) - which individually contributes to uremic cardiomyopathy, but each one also exacerbates the others
creating a self-amplifying unrelenting vortex. We focus on the model that Klotho deficiency and phosphotoxicity
exacerbate each other and both contribute to CVD. If we disrupt these disturbances simultaneously, it will be
much more effective than manipulating them alone thus furnishing a novel and efficacious regimen to prevent
and treat uremic cardiomyopathy. In Aim 1, we will use a well-established rodent model of CKD and uremic
cardiomyopathy to test this therapeutic approach. These are empiric but important proof-of-concept studies to
secure the utility of this approach. In Aim 2, we will examine the long sort after but yet unresolved question of
the underlying mechanism of Klotho deficiency in CKD. We know that uremia, Klotho deficiency exacerbates
phosphotoxicity by reducing phosphaturia but how Klotho is suppressed in CKD is not known. We will test the
model that phosphate loading causes systemic Klotho deficiency by at least two mechanisms: direct inhibition of
Klotho transcription via methylation of its promoter; and reduced Klotho shedding from the kidney using
combined in vivo and in vitro approaches. Although Klotho deficiency per se have been shown to pathologic
cardiac remodeling, the molecular mechanism(s) that mediate(s) its action is still an enigma. We constructed a
model and propose that one principal mechanism is the balance between autophagy and apoptosis and Klotho
holds the “toggle switch” by modifying the formation of the important autophagy complex Beclin 1/Bcl-2. In Aim
3, we will use both in vivo and in vitro models to test the paradigm. Using genetically modified animals, we will
manipulate autophagy levels and test whether the protective action of Klotho is mediated by enhanced
autophagy. We will use in vitro models to further test the model of phosphate loading and Klotho flipping the
toggle switch in opposite directions. The proposed studies will uncover some fundamental biologic mechanisms
of how Klotho is suppressed in CKD and phosphate loading, elucidate how Klotho protects the cell via autophagy
flux, and finally provide the critical pre-clinical data to form the foundation for translation to therapy in human
CKD and uremic cardiomyopathy.

## Key facts

- **NIH application ID:** 10179360
- **Project number:** 5R01DK091392-09
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ming-Chang Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2011-04-10 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179360

## Citation

> US National Institutes of Health, RePORTER application 10179360, Klotho and Phosphate in Chronic Kidney Disease: Pathogenesis and Therapeutics (5R01DK091392-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179360. Licensed CC0.

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