Thick Ascending Limb Specific Inactivation of Myh9 and Myh10 Myosin Motors Results in Progressive Kidney Disease and Drives Sex-specific Cellular Adaptation in the Distal Nephron and Collecting Duct.

Our previous work established a role for actin associated myosin motor proteins MYH9 and MYH10 in the trafficking of thick ascending limb (TAL) specific cargoes, uromodulin (UMOD) and Na + K + 2Cl- cotransporter (NKCC2). Here, we have generated a TAL-specific Myh9&10 conditional knockout (Myh9&10 TAL-cKO) mouse model to determine the cell autonomous roles for MYH9&10 proteins in TAL cargo transport and to understand the consequence of TAL dysfunction in the adult kidney. Myh9&10 TAL-cKO mice develop progressive kidney disease with pathological tubular injury confirmed by histological changes, tubular injury markers, upregulation of ER stress/unfolded protein response pathway, and higher blood urea nitrogen and serum creatinine. However, male mice survive twice as long as female mice. We determined that the sexual dimorphism in morbidity is due to adaptation of the distal nephron and the collecting ducts in response to TAL dysfunction and significantly lower NKCC2 expression. We demonstrate that this triggers a compensatory mechanism involving sex-specific cellular adaptation within the distal tubules and collecting ducts to boost sodium reabsorption. While both sexes overcompensate by activating ENaC expression in the medullary collecting ducts resulting in hypernatremia, this is subdued in male Myh9&10 TAL-cKO mice as they initially promote higher sodium chloride cotransporter (NCC) expression within the distal nephron. Our results indicate that compromised TAL function results in maladaptation of medullary collecting duct cells, which acquire cortical-like properties, including ENaC expression. This work further confirms a cell autonomous role for myosin motor proteins MYH9&10 in the maintenance of NKCC2 expression in the TAL and uncover adaptive mechanisms of the distal nephron and the collecting duct segments in response to TAL dysfunction.