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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096015-07
Application #
9791164
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2013-09-20
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Tsuji, Kenji; Suleiman, Hani; Miner, Jeffrey H et al. (2017) Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM). Sci Rep 7:11696
Lu, H A Jenny (2017) Diabetes Insipidus. Adv Exp Med Biol 969:213-225
Mamuya, Fahmy A; Cano-PeƱalver, Jose Luis; Li, Wei et al. (2016) ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway. Am J Physiol Renal Physiol 311:F1346-F1357
Cheung, Pui W; Nomura, Naohiro; Nair, Anil V et al. (2016) EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2-Mediated Renal Water Reabsorption. J Am Soc Nephrol :
Rice, William L; Li, Wei; Mamuya, Fahmy et al. (2015) Polarized Trafficking of AQP2 Revealed in Three Dimensional Epithelial Culture. PLoS One 10:e0131719
Arthur, Julian; Huang, Jianmin; Nomura, Naohiro et al. (2015) Characterization of the putative phosphorylation sites of the AQP2 C terminus and their role in AQP2 trafficking in LLC-PK1 cells. Am J Physiol Renal Physiol 309:F673-9
Nomura, Naohiro; Nunes, Paula; Bouley, Richard et al. (2014) High-throughput chemical screening identifies AG-490 as a stimulator of aquaporin 2 membrane expression and urine concentration. Am J Physiol Cell Physiol 307:C597-605
P?unescu, Teodor G; Lu, Hua A J; Russo, Leileata M et al. (2013) Vasopressin induces apical expression of caveolin in rat kidney collecting duct principal cells. Am J Physiol Renal Physiol 305:F1783-95
Brown, Dennis; Lu, Hua A Jenny (2013) Aquaporin-2 inhibitors: fishing in the chemical pool. J Am Soc Nephrol 24:685-6

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