Renomedullary Interstitial Cell Endothelin A Receptors Regulate BP and Renal Function

Significance Statement The functional significance of renomedullary interstitial cells, which are uniquely and abundantly expressed in the renal inner medulla, is largely unknown. In vitro studies have demonstrated that endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function. Using a novel mouse model with inducible renomedullary interstitial cell–specific endothelin A receptor gene targeting, the authors found that compared with control mice, mice lacking endothelin A receptors in renomedullary interstitial cells exhibited reduced BP, enhanced natriuresis and diuresis, increased endogenous natriuretic and diuretic factor production, and reduced medullary transporter expression. These studies identify a role for renomedullary interstitial cells in vivo in regulating renal function under physiologic conditions. Background The physiologic role of renomedullary interstitial cells, which are uniquely and abundantly found in the renal inner medulla, is largely unknown. Endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function in vitro . Methods To assess the effect of targeting renomedullary interstitial cell endothelin A receptors in vivo , we generated a mouse knockout model with inducible disruption of renomedullary interstitial cell endothelin A receptors at 3 months of age. Results BP and renal function were similar between endothelin A receptor knockout and control mice during normal and reduced sodium or water intake. In contrast, on a high-salt diet, compared with control mice, the knockout mice had reduced BP; increased urinary sodium, potassium, water, and endothelin-1 excretion; increased urinary nitrite/nitrate excretion associated with increased noncollecting duct nitric oxide synthase-1 expression; increased PGE 2 excretion associated with increased collecting duct cyclooxygenase-1 expression; and reduced inner medullary epithelial sodium channel expression. Water-loaded endothelin A receptor knockout mice, compared with control mice, had markedly enhanced urine volume and reduced urine osmolality associated with increased urinary endothelin-1 and PGE 2 excretion, increased cyclooxygenase-2 protein expression, and decreased inner medullary aquaporin-2 protein content. No evidence of endothelin-1–induced renomedullary interstitial cell contraction was observed. Conclusions Disruption of renomedullary interstitial cell endothelin A receptors reduces BP and increases salt and water excretion associated with enhanced production of intrinsic renal natriuretic and diuretic factors. These studies indicate that renomedullary interstitial cells can modulate BP and renal function under physiologic conditions.