# Physiologic regulation of soluble Klotho levels by systemic acid/base status

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2022 · —

## Abstract

Chronic kidney disease (CKD) frequently progresses to end-stage renal disease accompanied by complications
including cardiac hypertrophy, accelerated vascular disease, ectopic calcification, endothelial dysfunction,
osteodystrophy, sarcopenia, skin atrophy, and renal fibrosis. Factors including hypertension, volume-overload,
acidosis, chronic low-grade inflammation, disordered Ca and PO4 metabolism, elevated PTH and FGF23 levels,
and reduced circulating Klotho (sKlotho) levels are associated with CKD. HCO3 supplementation or alkaline
diets (eg. DASH diet) slow progression of CKD even in stages 3 and 4. The mechanism(s) by which HCO3
supplementation or alkaline diets work are unknown. The goal of these studies is to identify physiologic
mechanisms that can slow or reverse the course of CKD. sKlotho is normally produced by the kidney and
released into the circulation, preserves renal function, and prevents many of the systemic complications of renal
failure. As renal disease progresses serum and urine sKlotho levels fall, and patients acquire characteristics
resembling the premature aging phenotype of Klotho-/- mice. The kidney is the source of sKlotho as demonstrated
by findings that Klotho levels are high in the renal vein, bilateral nephrectomy lowers sKlotho, and mice with
kidney-specific Klotho deletion have patterns of disease that are phenotypically indistinguishable from Klotho-/-
mice. Possible physiologic mechanisms by which sKlotho levels might be regulated have not been defined. We
discovered that in intact mice and rats, mouse renal cortical homogenates, and cultured cells, calcium-sensing
receptor (CaSR) activation increases sKlotho levels via ADAM10-mediated shedding. The ability of ligands to
activate the CaSR is modified by pH with an alkaline pH environment increasing, and an acid pH environment
decreasing CaSR signaling. We found that an alkali load increases CaSR signaling and sKlotho in mice and rats,
and that an alkaline milieu increases Klotho shedding in mouse kidney homogenates and cultured cells in a
CaSR-dependent manner, and that oral K citrate for 72 hrs increases serum and urine Klotho in human
volunteers. These results define a novel physiologic mechanism for regulation of sKlotho levels by the renal
CaSR and pH. We hypothesize that acidosis accelerates, and alkalinization slows the rate of loss of renal
function in CKD because acidosis decreases, and alkalinity increases renal CaSR-stimulated Klotho
shedding from the kidney. The hypothesis will be developed with studies in: 1) mice, CaSR-/- mice, renal
homogenates, cultured cells, that will demonstrate that renal Klotho shedding is regulated by the CaSR in
response to CaSR ligands and pH; 2) CKD disease models to show that alkali treatment increases sKlotho levels
and reduces renal injury and cardiac hypertrophy, and 3) renal tissue and cultured cells to define the mechanisms
that permit the CaSR, Klotho, and ADAM10 to interact focusing on the C8 tetraspanin family.

## Key facts

- **NIH application ID:** 10454775
- **Project number:** 5I01BX004691-03
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** Richard Tyler Miller
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454775

## Citation

> US National Institutes of Health, RePORTER application 10454775, Physiologic regulation of soluble Klotho levels by systemic acid/base status (5I01BX004691-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454775. Licensed CC0.

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