# Integrin binding proteins and the kidney

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

This proposal aims to define the role of two major β1 integrin binding proteins, talins and kindlins, in regulating
kidney tubule responses to injury. Integrins are comprised of 18 α and 8 β subunits combined in a restricted
manner to form various heterodimers, each of which exhibits different binding properties to extracellular matrix
(ECM) components. β1, the most abundantly expressed integrin subunit in the kidney, binds 12 α subunits. Its
cytoplasmic tail (CT) interacts with multiple proteins that promote integrin-mediated adhesion, migration and
bidirectional signaling. Talins and kindlins are the best defined molecules that promote integrin activation. Two
talin and 2 kindlin isoforms expressed in kidney bind to 2 canonical NxxY motifs found in most β integrin tails:
talins to the membrane-proximal motif and kindlins to the membrane distal. We showed that deleting β1 integrin
at the initiation of collecting system development caused dysmorphic and dysplastic kidneys, while removing β1
post development did not result in morphological abnormalities, but caused severe tubulointerstitial fibrosis
following unilateral ureteric obstruction (UUO). Similarly, deletion of β1 from the proximal kidney tubule post-
development did not result in morphological defects, but there was a major urine-concentrating deficiency and
increased susceptibility and failure of recovery from acute injury. Surprisingly, when we deleted either all talin or
kindlin isoforms in the developing collecting system, the mice were anephric. These phenotypes, which are much
more severe than when β1 integrin was deleted, suggest that talins and kindlins have functions that extend
beyond those involving their ability to bind and activate β1 integrin. We therefore developed tools to define the
specific roles of the various talin and kindlin isoforms in mediating and/or resolving kidney injury. In this grant we
will utilize these tools to test the hypothesis that talins and kindlins regulate the response of kidney tubules
to injury by distinct β1 integrin-dependent and -independent mechanisms. This hypothesis will be tested
in the following 2 aims.
Aim 1. Determine the mechanisms whereby talins regulate the response of kidney tubules to injury. How
talins modulate the response of the kidney to tubular injury will be tested in UUO and prolonged ischemia
reperfusion models and mechanistic studies will be performed on polarized renal tubule epithelial cells.
Aim 2. Determine the mechanisms whereby kindlins regulate the response of kidney tubules to injury.
We will contrast the response to injury of talin and kindlin mice as well as their differences in their cell function,
to define the distinct roles and mechanisms of action of these proteins in renal tubular epithelial biology and
pathology.

## Key facts

- **NIH application ID:** 9864023
- **Project number:** 5I01BX002196-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** ROY ZENT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864023

## Citation

> US National Institutes of Health, RePORTER application 9864023, Integrin binding proteins and the kidney (5I01BX002196-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864023. Licensed CC0.

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