# Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $437,080

## Abstract

PROJECT SUMMARY/ABSTRACT
Kidney stones affect 9% of the population and idiopathic hypercalciuria is the major pathogenic risk factor. Our
long-term goal is to elucidate the pathogenesis of idiopathic hypercalciuria and develop novel therapies. The
renal proximal tubule reabsorbs 70% of filtered calcium, which is believed to occur via the paracellular pathway.
Claudin-2 is a paracellular cation channel that is expressed in the proximal renal tubule and in intestinal
epithelium. In preliminary studies, we show that claudin-2 knockout mice have renal and absorptive
hypercalciuria, leading to severe papillary nephrocalcinosis. Moreover, we find that claudin-2 gene variants are
associated with kidney stone disease in humans. We hypothesize that claudin-2 mediates calcium reabsorption
in the proximal tubule and calcium secretion in the colon. Loss of claudin-2 increases calcium delivery to the
loop of Henle, and predisposes to inner medullary calcium deposition and hence kidney stone disease. The
specific aims to test this hypothesis are: (1) Test whether claudin-2 mediates paracellular calcium reabsorption
in the renal proximal tubule. We will use tubule micropuncture of claudin-2 global knockout mice, determine the
contribution of the proximal tubule with kidney-specific conditional knockout mice, test the role of claudin-2 in the
hypocalciuric effect of thiazides, and explore the effect of sex. (2) Test whether claudin-2 mediates intestinal
secretion of calcium. We will generate intestine-specific claudin-2 knockout mice and perform tracer flux assays
in everted intestinal sacs and Ussing chamber preparations. (3) Test whether human claudin-2 gene variants
and protein expression are associated with urine calcium and kidney stones. We will conduct a gene association
study in 3 U.S. population-based cohorts to test the association of claudin-2 gene polymorphisms with a history
of kidney stones and calcium excretion. In a separate cohort of kidney stone formers and matched normal
volunteers, we will test the association of claudin-2 protein abundance in urinary exosomes with hypercalciuric
kidney stone disease.

## Key facts

- **NIH application ID:** 10020951
- **Project number:** 5R01DK115727-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Alan S Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,080
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020951

## Citation

> US National Institutes of Health, RePORTER application 10020951, Role of claudin-2 in Calcium Homeostasis and Kidney Stone Disease (5R01DK115727-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020951. Licensed CC0.

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