Two Mineralocorticoid Receptor–Mediated Mechanisms of Pendrin Activation in Distal Nephrons
Authors: Ayuzawa Nobuhiro , Nishimoto Mitsuhiro , Ueda Kohei , Hirohama Daigoro , Kawarazaki Wakako , Shimosawa Tatsuo , Marumo Takeshi , Fujita Toshiro 
Published: February 2020

Significance Statement

Pendrin expressed in renal β-intercalated cells is involved in sodium chloride reabsorption in distal nephron, and plays an essential role in fluid homeostasis and BP control in conjunction with sodium chloride cotransporter in distal convoluted tubules. Using intercalated cell–specific mineralocorticoid receptor knockout mice, the authors found two distinct pathways of pendrin activation: by angiotensin II elevation, mediated by mineralocorticoid receptor in intercalated cells, and by hypokalemic alkalosis, mediated by mineralocorticoid receptor in principal cells. Moreover, they demonstrated that pendrin activation, in cooperation with sodium chloride cotransporter, contributes to the maintenance of fluid homeostasis during dietary salt restriction and to the development of salt-sensitive hypertension during aldosterone excess. They also clarified that activation of mineralocorticoid receptor at the two nephron sites plays a key role in thiazide-resistant hypertension.

Background

Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system.

Methods

Using mice with mineralocorticoid receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via mineralocorticoid receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension.

Results

Deletion of mineralocorticoid receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell–specific mineralocorticoid receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of mineralocorticoid receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated mineralocorticoid receptor–epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP.

Conclusions

In conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through mineralocorticoid receptor activation in intercalated cells and by alkalosis through mineralocorticoid receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.