Novel role(s) for Nonmuscle Myosin 2 isoforms Myh9 and Myh10 in renal epithelial cells and tubular disease.
Authors: Chandrasekar Indra , Otterpohl Karla L , Hart Ryan G , Evans Claire , Phillips Carrie , Molitoris Bruce A , Surendran Kameswaran 
Published: June 2021

Nonmuscle Myosin 2 (NM2) is an actin associated motor protein that is essential for cellular processes like adhesion, migration, polarity, and division. The NM2 family is composed of three isoforms, NM2A, NM2B, and NM2C encoded by genes Myh9, Myh10 and Myh14 respectively. Each of these isoforms have both unique and redundant functions due to differences in their affinities for actin and ATPase activities. Our previous work demonstrated a novel role for Myh9&10 in both compensatory and constitutive clathrin mediated endocytosis. Previous studies have shown that point mutations in the NM2A gene, MYH9, are associated with human disease involving blood, eye, ear and kidney disorders. We hypothesized that the underlying mechanism in MYH9 related kidney disorders is compromised renal epithelial endocytosis and transport. Consistent with the hypothesis all three NM2 isoforms have unique membrane associated expression and localization pattern along the nephron and collecting duct segments. While, Myh9 expression was limited to the apical membrane of the TAL segment of the loop of Henle, Myh10 and Myh14 isoforms had much broader expression pattern along the tubular segments. All isoforms shared distinct localization to the apical and/or basolateral membranes along the renal tubules and presented a micro‐domain like pattern in some tubular segments. Interestingly, in the collecting duct segment, Myh10 and Myh14 are uniquely expressed in principal and intercalated cells, respectively. The distinct localization of the NM2 isoforms within the epithelial cells of the renal tubules suggests that each isoform has a unique function and loss of each isoform may lead to specific pathophysiology. Inducible conditional genetic inactivation (cKO) of Myh9, Myh10, and both Myh9&10 within the renal tubules of adult mice using the doxycycline inducible Pax8‐>rtTA; Tet‐O‐Cre system revealed critical roles of Myh9 and Myh10 in the renal tubular segments. Histological evaluation showed that Myh9 cKO mice had mild tubular dilation by 12 weeks of age with infiltrating cells that progressed to tubulointerstitial disease over time. The Myh9&10 cKO mice show decreased urine pH and increased blood urea nitrogen and serum creatinine levels by 9 weeks of age. Histological analysis revealed tubular dilation, cellular infiltration, inflammation as well as glomerular defects by 12 weeks of age and mice were moribund by 4 – 5 months of age. Preliminary results indicate loss of GPI‐anchored protein, Uromodulin from the apical membrane of the TAL tubules in Myh9 and Myh9&10 cKO mice. We are beginning to characterize the localization pattern of membrane‐associated channels (ROMK) and co‐transporters (NKCC2) in these mouse models and our results indicate changes in their localization pattern along the tubular segments. Our mouse models demonstrate a novel and critical role for NM2 isoforms in maintaining renal tubular function in the adult mouse kidney. We envision that NM2 isoforms participate in anchoring, targeting, and/or transport of membrane associated proteins in the tubular epithelial cells and loss of function of NM2 isoforms results in progressive tubular disease.

Support or Funding Information

Funding for this project and the Core facilities at Sanford Research are through NIH COBRE grants (P20GM103620 and P20GM103548) as well as Sanford Research program funds.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.