Vascular control of kidney epithelial transporters

Abstract

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT₁) receptors in the kidney, stimulating Na⁺ reabsorption. AT₁ receptors in tubular epithelia control expression and stimulation of Na⁺ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT₁ receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na⁺ excretion in SMKO mice, we considered whether alterations in Na⁺ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na⁺ 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 SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser⁷¹), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na⁺ channel. However, the increases in α- and γ-epithelial Na⁺ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na⁺ excretion observed after cell-specific deletion of AT₁ receptors from smooth muscle cells is associated with altered Na⁺ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na⁺ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

Keywords: amiloride; angiotensin; epithelial Na+ channel; furosemide; hypertension.