Two Mineralocorticoid Receptor-Mediated Mechanisms of Pendrin Activation in Distal Nephrons.

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 ß-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.

Preliminary analysis of the relationship between serum lutein and zeaxanthin levels and macular pigment optical density.

PURPOSE: To assess the relationship between combined serum lutein and zeaxanthin (L+Z) concentration and macular pigment optical density (MPOD), and to investigate the effect of L+Z+docosahexaenoic acid (DHA) dietary supplementation on the spatial distribution of MPOD. METHODS: Twenty healthy fellow eyes with unilateral wet age-related macular degeneration or chronic central serous chorioretinopathy were included. All participants received a dietary supplement for 6 months that contained 20 mg L, 1 mg Z, and 200 mg DHA. The best-corrected visual acuity and contrast sensitivity (CS) were measured at baseline and at 1, 3, and 6 months. Serum L+Z concentrations were measured at baseline and at 3 months. MPOD was calculated at each time point using fundus autofluorescent images. RESULTS: Serum L+Z concentration was correlated with MPOD at 1°-2° eccentricity at baseline (r=0.63, P=0.003) and 3 months (r=0.53, P=0.015). Serum L+Z concentration increased by a factor of 2.3±1.0 (P<0.0001). At 6 months, MPOD was significantly higher compared to the baseline level at 0°-0.25° (P=0.034) and 0.25°-0.5° (P=0.032) eccentricity. CS improved after 3 or 6 months of L+Z+DHA supplementation (P<0.05). CONCLUSION: Juxtafoveal MPOD was associated with serum L+Z concentration. Foveal MPOD was increased by L+Z+DHA dietary supplementation.

Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation.

Experiments with hyperaldosteronemic animals suggest that, despite lowering plasma aldosterone, salt worsens renal injury by paradoxical activation of the mineralocorticoid receptor (MR). Salt and aldosterone synergistically contribute to renal impairment through Rac1-mediated activation of the MR, but whether angiotensin II also promotes renal injury through this mechanism is unknown. Here, we placed angiotensin II-overproducing double transgenic Tsukuba hypertensive mice on a low- or high-salt intake for 6 weeks and treated some animals with adrenalectomy, the MR antagonist eplerenone, the Rac inhibitor EHT1864, or hydralazine. High-salt intake, but not low-salt intake, led to hypertension and prominent kidney injury. Adrenalectomy prevented angiotensin II/salt-induced nephropathy in mice receiving high-salt intake, which was recapitulated by aldosterone supplementation, suggesting the involvement of aldosterone/MR signaling. Plasma aldosterone levels, however, were lower in high- than low-salt conditions. Instead, angiotensin II/salt-evoked MR activation associated with Rac1 activation and was not dependent on plasma aldosterone level. Both EHT1864 and eplerenone repressed the augmented MR signaling and mitigated kidney injury with partial but significant reduction in BP with high-salt intake. Hydralazine similarly reduced BP, but it neither suppressed the Rac1-MR pathway nor ameliorated the nephropathy. Taken together, these results show that angiotensin II and salt accelerate kidney injury through Rac1-mediated MR activation. Rac inhibition may be a promising strategy for the treatment of CKD.