Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease
Actin-associated nonmuscle myosin II (NM2) motor proteins play critical roles in a myriad of cellular functions, including endocytosis and organelle transport pathways. Cell type–specific expression and unique subcellular localization of the NM2 proteins, encoded by the Myh9 and Myh10 genes, in the...
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American Society for Clinical investigation
2020-11-01
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Online Access: | https://doi.org/10.1172/jci.insight.138530 |
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doaj-752c724f1621421da97c4604226a75202021-08-02T17:47:09ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-11-01521Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney diseaseKarla L. OtterpohlBrook W. BusselmanIshara RatnayakeRyan G. HartKimberly R. HartClaire M. EvansCarrie L. PhillipsJordan R. BeachPhil AhrenkielBruce A. MolitorisKameswaran SurendranIndra ChandrasekarActin-associated nonmuscle myosin II (NM2) motor proteins play critical roles in a myriad of cellular functions, including endocytosis and organelle transport pathways. Cell type–specific expression and unique subcellular localization of the NM2 proteins, encoded by the Myh9 and Myh10 genes, in the mouse kidney tubules led us to hypothesize that these proteins have specialized functional roles within the renal epithelium. Inducible conditional knockout (cKO) of Myh9 and Myh10 in the renal tubules of adult mice resulted in progressive kidney disease. Prior to overt renal tubular injury, we observed intracellular accumulation of the glycosylphosphatidylinositol-anchored protein uromodulin (UMOD) and gradual loss of Na+ K+ 2Cl– cotransporter from the apical membrane of the thick ascending limb epithelia. The UMOD accumulation coincided with expansion of endoplasmic reticulum (ER) tubules and activation of ER stress and unfolded protein response pathways in Myh9&10-cKO kidneys. We conclude that NM2 proteins are required for localization and transport of UMOD and loss of function results in accumulation of UMOD and ER stress–mediated progressive renal tubulointerstitial disease. These observations establish cell type–specific role(s) for NM2 proteins in regulation of specialized renal epithelial transport pathways and reveal the possibility that human kidney disease associated with MYH9 mutations could be of renal epithelial origin.https://doi.org/10.1172/jci.insight.138530Cell biologyNephrology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Karla L. Otterpohl Brook W. Busselman Ishara Ratnayake Ryan G. Hart Kimberly R. Hart Claire M. Evans Carrie L. Phillips Jordan R. Beach Phil Ahrenkiel Bruce A. Molitoris Kameswaran Surendran Indra Chandrasekar |
spellingShingle |
Karla L. Otterpohl Brook W. Busselman Ishara Ratnayake Ryan G. Hart Kimberly R. Hart Claire M. Evans Carrie L. Phillips Jordan R. Beach Phil Ahrenkiel Bruce A. Molitoris Kameswaran Surendran Indra Chandrasekar Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease JCI Insight Cell biology Nephrology |
author_facet |
Karla L. Otterpohl Brook W. Busselman Ishara Ratnayake Ryan G. Hart Kimberly R. Hart Claire M. Evans Carrie L. Phillips Jordan R. Beach Phil Ahrenkiel Bruce A. Molitoris Kameswaran Surendran Indra Chandrasekar |
author_sort |
Karla L. Otterpohl |
title |
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
title_short |
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
title_full |
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
title_fullStr |
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
title_full_unstemmed |
Conditional Myh9 and Myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
title_sort |
conditional myh9 and myh10 inactivation in adult mouse renal epithelium results in progressive kidney disease |
publisher |
American Society for Clinical investigation |
series |
JCI Insight |
issn |
2379-3708 |
publishDate |
2020-11-01 |
description |
Actin-associated nonmuscle myosin II (NM2) motor proteins play critical roles in a myriad of cellular functions, including endocytosis and organelle transport pathways. Cell type–specific expression and unique subcellular localization of the NM2 proteins, encoded by the Myh9 and Myh10 genes, in the mouse kidney tubules led us to hypothesize that these proteins have specialized functional roles within the renal epithelium. Inducible conditional knockout (cKO) of Myh9 and Myh10 in the renal tubules of adult mice resulted in progressive kidney disease. Prior to overt renal tubular injury, we observed intracellular accumulation of the glycosylphosphatidylinositol-anchored protein uromodulin (UMOD) and gradual loss of Na+ K+ 2Cl– cotransporter from the apical membrane of the thick ascending limb epithelia. The UMOD accumulation coincided with expansion of endoplasmic reticulum (ER) tubules and activation of ER stress and unfolded protein response pathways in Myh9&10-cKO kidneys. We conclude that NM2 proteins are required for localization and transport of UMOD and loss of function results in accumulation of UMOD and ER stress–mediated progressive renal tubulointerstitial disease. These observations establish cell type–specific role(s) for NM2 proteins in regulation of specialized renal epithelial transport pathways and reveal the possibility that human kidney disease associated with MYH9 mutations could be of renal epithelial origin. |
topic |
Cell biology Nephrology |
url |
https://doi.org/10.1172/jci.insight.138530 |
work_keys_str_mv |
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