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 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.
Key Topics Include:
- The role of vascular angiotensin receptors in establishing basal blood pressure
- Vascular angiotensin receptor modulation of sodium excretion in the kidney
- How blood pressure and not angiotensin receptors contribute to cardiac hypertrophy in hypertension
- The role of the renin-angiotensin system to blood pressure control
- The compensatory mechanisms contribute to blood pressure regulation in absence of angiotensin receptors
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