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

Claudin-2 在钙稳态和肾结石疾病中的作用

基本信息

批准号：
10238078
负责人：
Alan S Yu
金额：
$ 31.08万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238078
关键词：
Affect Attention Back Biological Assay Calcium Cations Colon Crystallization Data Defect Deposition Development Disease Distal Frequencies Gene Proteins Genes Genetic Polymorphism Genotype Goals Henle&apos s loop Homeostasis Human Intercellular Junctions Intestinal Secretions Intestines Ion Channel Kidney Kidney Calculi Knockout Mice Lead Limb structure Lithium Mediating Micropuncture Modeling Mus Nature Nephrocalcinosis Nephrolithiasis Papillary Pathogenesis Pathogenicity Pathway interactions Patients Permeability Phenotype Population Preparation Proteins Proximal Kidney Tubules Recording of previous events Renal tubule structure Risk Risk Factors Role Route Site Testing Thinness Tight Junctions Tissues Tracer Urinary Calculi Urine Western Blotting calcium excretion cohort conditional knockout exosome genetic variant hypercalciuria insight intestinal epithelium novel novel therapeutic intervention novel therapeutics population based protein expression radiotracer renal calcium sex thiazide urinary volunteer

项目摘要

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.

项目总结/文摘