# Hypercalciuria and TRPV6-mediated Active Calcium Reabsorption in the Proximal Tubule

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $334,125

## Abstract

PROJECT SUMMARY
Hypercalciuria occurs in 5-10% of the population and is the most common cause of calcium (Ca) kidney stone
disease. Ca reabsorption takes place in different nephron segments; however, evidence from human subjects
indicates that proximal tubule Ca reabsorption is decreased in stone formers. Furthermore, studies in both
animals and humans suggest that increased proximal tubule Ca reabsorption accounts for the hypocalciuric
effect of thiazide diuretics, the first line medication for hypercalciuria. Compared to Ca reabsorption in the distal
tubule, much less is known about the mechanism of Ca reabsorption in the proximal tubule. Lines of evidence
from classical physiological studies indicate the existence of an active Ca transport pathway in the proximal
straight tubule, the last portion of the proximal tubule where Ca can be reabsorbed before tubular fluid enters the
loop of Henle where supersaturation of Ca phosphate may occur due to water extraction. Active Ca reabsorption
in this segment of the nephron may remove Ca in the tubular fluid to a level below that in the plasma. The
objective of this proposal is to elucidate the roles of a novel active Ca transport pathway in the proximal straight
tubule in causing and treating hypercalciuria. The central hypothesis is that active Ca reabsorption in the
proximal tubule is disrupted by postprandial insulin surge and under hyperinsulinemia and is enhanced by
thiazides. In addition, a Ca channel in the apical side of proximal straight tubule may act as a Ca sensor to
regulate overall Ca homeostasis. It has been shown that postprandial insulin secretion and Ca excretion are both
increased in hypercalciuric stone formers. Our preliminary studies indicate that TRPV6, a key Ca channel in the
transcellular Ca transport pathway, is distributed to the proximal straight tubule, and TRPV6 activity is inhibited by
insulin, and the hypocalciuric effect of hydrochlorothiazide is significantly reduced in TRPV6 null mice. These
observations support our hypothesis, which implies that inhibition of TRPV6 by insulin contributes to postprandial
hypercalciuria and hypercalciuria due to compensatory hyperinsulinemia as a result of insulin resistance. We will
test our hypothesis and achieve our research objective by pursuing the following specific aims. 1. Determine the
inhibitory effect of insulin on active Ca reabsorption in the proximal tubule. 2. Determine to what extent TRPV6
mediates the hypocalciuric effect of thiazides. 3. Determine the Ca-sensor roles of TRPV6 in the proximal
straight tubule that regulate vitamin D synthesis and paracellular Ca transport. Approaches ranging from Ca
influx in human proximal tubule cells to metabolic studies using TRPV6 null mice will be employed to accomplish
our research goals. Upon successful completion of the proposed research, we expect to unveil the molecular
mechanism for the active Ca reabsorption in the proximal tubule that regulates Ca reabsorption and Ca
home...

## Key facts

- **NIH application ID:** 9899982
- **Project number:** 5R01DK104924-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JI-BIN PENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,125
- **Award type:** 5
- **Project period:** 2017-07-25 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899982

## Citation

> US National Institutes of Health, RePORTER application 9899982, Hypercalciuria and TRPV6-mediated Active Calcium Reabsorption in the Proximal Tubule (5R01DK104924-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899982. Licensed CC0.

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