# Novel roles of integrin b1 signaling in regulating principal cell function andmaintaining collecting duct integrity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $372,960

## Abstract

The water channel aquaporin-2 (AQP2) is a major water channel that mediates water transport in the collecting
ducts (CDs) of the kidney in response to the antidiuretic hormone (ADH), also called vasopressin (VP). We and
others have studied extensively the AQP2 trafficking and its regulatory mechanism(s) for many years. In the
past 5 years, our studies have uncovered several important and previously unrecognized aspects of AQP2: 1)
AQP2 unexpectedly interacts with the adhesion molecule and major extracellular matrix (ECM) receptor, β1
integrin. Through interaction with β1 integrin, AQP2 modulates the trafficking of β1 integrin and promotes
tubular cell migration; 2) Polarized AQP2 trafficking to the apical membrane involves basolateral insertion and
redirection via transcytosis, and therefore, is potentially subjected to regulatory cues from the ECM; 3) More
recently, we have identified that a major downstream target of the integrin signaling pathway, integrin-linked
kinase (ILK) regulates AQP2 recycling via modulating the actin cytoskeleton. These data open a novel aspect
of a close interplay of AQP2 trafficking and integrin-ECM signaling, and the importance of their interaction
in modulating epithelial structure and function. To understand it further, we generated transgenic animals with
a deletion of β1 integrin specifically in the principal cells (PCs) in the kidney collecting ducts. Very interestingly,
we have found that deleting β1 integrin in the CD PCs causes significant tubular injury and interstitial fibrosis
with significantly activated TGF-β signaling cascade. KO mice develop renal failure and early mortality at 6-8
weeks of age. In addition, the young KO and adult hemizygous KO mice presented with highly concentrated
urine and impaired capability of water diuresis. There was a significant and persistent apical membrane
accumulation of AQP2 in the CD PCs in the homo- and hemizygous β1 integrin KO mice. Based on these two
intriguing observations, we proposed a comprehensive research program to 1) determine the critical function of
PC specific β1 integrin signaling in maintaining collecting duct integrity, and dissect specifically, the epithelial
mechanism(s) contributing to TGF-β activation and subsequent interstitial fibrosis in the β1 integrin KO
animals; and 2) characterize the novel regulatory role of β1 integrin signaling in AQP2 trafficking in cells and
urine concentration in the kidney. Our proposed studies are logically integrated and focus on two important
processes of acute CD injury/fibrosis and water retention. Cross talk between AQP2 and β1 integrin could,
therefore, be involved in mediating both cell injury and water reabsorption. They will contribute importantly to
better understanding the fundamentally critical, but overlooked epithelial factors that initiate and promote
fibrogenesis in kidney. They will also uncover a novel ECM-integrin mediated regulatory mechanism for water
transport in the kidney. It could serve as a...

## Key facts

- **NIH application ID:** 10220019
- **Project number:** 5R01DK096015-09
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HUA A LU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,960
- **Award type:** 5
- **Project period:** 2013-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220019

## Citation

> US National Institutes of Health, RePORTER application 10220019, Novel roles of integrin b1 signaling in regulating principal cell function andmaintaining collecting duct integrity (5R01DK096015-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220019. Licensed CC0.

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