Matthew Sparks, MD, explores the vascular-tubular crosstalk in the renin-angiotensin system that may play a key role in the regulation of pressure natriuresis.

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, Dr. Sparks' team 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, they considered whether alterations in Na⁺ transporter expression might also play a role.

Using proteomic analysis, they found 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, they 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 Œ±- and Œ≥-epithelial Na⁺ channel. However, the increases in Œ±- and Œ≥-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.