Vascular Control of Kidney Epithelial Transporters.

A major pathway in hypertension pathogenesis involves direct activation of Ang II (AT1) receptors in the kidney, stimulating sodium reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of sodium transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKOs). While impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary sodium excretion in SMKOs, we considered whether alterations in sodium transporter expression might also play a role and therefore carried out a proteomic analysis of key sodium transporters and associated proteins. Here we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKOs, accompanied by attenuated natriuretic and diuretic responses to furosemide. During Ang II hypertension, we find widespread remodeling of transporter expression in wild-type mice with significant increases in levels of total NCC, phosphorylated-NCCps71, and NKCC2-P, along with the cleaved, activated forms of the a- and g-ENaC. However, the increases in a- and g-ENaC with Ang II were substantially attenuated in SMKOs. This was accompanied by reduced natriuretic response to amiloride. Thus, enhanced urinary sodium excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered sodium transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial cross-talk in the kidney, modulating expression of sodium transporters and contributing to regulation of pressure-natriuresis.