Rho GAP myosin IXa is a regulator of kidney tubule function

• Published in: American journal of physiology. Renal physiology Vol. 309; no. 6; pp. F501 - F513
• Main Authors: Thelen, Sabine, Abouhamed, Marouan, Ciarimboli, Giuliano, Edemir, Bayram, Bähler, Martin
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.09.2015
• Subjects: Albumins - metabolism; Animals; Carrier Proteins - metabolism; Cells; Cells, Cultured; Endocytosis - physiology; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - physiology; Hydronephrosis - genetics; Hydronephrosis - metabolism; Kidney diseases; Kidney Tubules - anatomy & histology; Kidney Tubules - cytology; Kidney Tubules - physiology; LLC-PK1 Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular weight; Myosins - genetics; Myosins - physiology; Nephrons - physiology; Polyuria - genetics; Polyuria - metabolism; Proteins; rho-Associated Kinases - metabolism; Rodents; Swine; Vasopressins - metabolism; proximal tubule; proteinuria; Rho signaling; Rho GTPase-activating protein; myosin 9a
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00220.2014

Mammalian class IX myosin Myo9a is a single-headed, actin-dependent motor protein with Rho GTPase-activating protein activity that negatively regulates Rho GTPase signaling. Myo9a is abundantly expressed in ciliated epithelial cells of several organs. In mice, genetic deletion of Myo9a leads to the formation of hydrocephalus. Whether Myo9a also has essential functions in the epithelia of other organs of the body has not been explored. In the present study, we report that Myo9a-deficient mice develop bilateral renal disease, characterized by dilation of proximal tubules, calyceal dilation, and thinning of the parenchyma and fibrosis. These structural changes are accompanied by polyuria (with normal vasopressin levels) and low-molecular-weight proteinuria. Immunohistochemistry revealed that Myo9a is localized to the circumferential F-actin belt of proximal tubule cells. In kidneys lacking Myo9a, the multiligand binding receptor megalin and its ligand albumin accumulated at the luminal surface of Myo9a-deficient proximal tubular cells, suggesting that endocytosis is dysregulated. In addition, we found, surprisingly, that levels of murine diaphanous-related formin-1, a Rho effector, were decreased in Myo9a-deficient kidneys as well as in Myo9a knockdown LLC-PK1 cells. In summary, deletion of the Rho GTPase-activating protein Myo9a in mice causes proximal tubular dilation and fibrosis, and we speculate that downregulation of murine diaphanous-related formin-1 and impaired protein reabsorption contribute to the pathophysiology.