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, ?1 integrin. Through interaction with ?1 integrin, AQP2 modulates the trafficking of ?1 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 ?1 integrin specifically in the principal cells (PCs) in the kidney collecting ducts. Very interestingly, we have found that deleting ?1 integrin in the CD PCs causes significant tubular injury and interstitial fibrosis with significantly activated TGF-? 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 ?1 integrin KO mice. Based on these two intriguing observations, we proposed a comprehensive research program to 1) determine the critical function of PC specific ?1 integrin signaling in maintaining collecting duct integrity, and dissect specifically, the epithelial mechanism(s) contributing to TGF-? activation and subsequent interstitial fibrosis in the ?1 integrin KO animals; and 2) characterize the novel regulatory role of ?1 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 ?1 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 local regulator of water homeostasis in response to hemodynamic and volume changes.
We will study how an adhesion molecule integrin beta1 in mouse kidney tubules causes kidney tubular injury and renal failure in mice. In addition, we will uncover how integrin beta 1 signaling regulates water absorption in mouse kidney, and identify a novel therapeutic target for treating disorders of water imbalance.
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