Lipocalin-2 deficiency protects against aldosterone-induced hypertension and organ damages by inhibiting mineralocorticoid receptor signaling

Abstract

Lipocalin-2, an adipokine dysregulated in cardiometabolic syndrome, is causatively involved in the development of obesity-related endothelial dysfunction and hypertension. The present study investigated the contribution of lipocalin-2 to aldosterone-induced pathologies involving mineralocorticoid receptors (MR). Mice were treated during four weeks with vehicle, angiotensin II or challenged with the combination of aldosterone plus uninephrectomy and administration of 1% saline in the drinking water (ANS). In mice without lipocalin-2 (LKO), the gene expression levels of MR in heart, kidney, adipose tissue and aorta are significantly lower than those of wild-type (WT) controls. ANS significantly increased arterial blood pressures in WT but not LKO mice. Moreover, lipocalin-2 deficiency prevented ANS-induced fibrotic damages in heart and kidneys. Treatment with the MR antagonist, spironolactone, protected mice against ANS-induced hypertension and organ damages to a similar extent as lipocalin-2-deficiency. On the other hand, angiotensin II-induced elevation of blood pressure was not affected significantly by either lipocalin-2-deficiency or MR inhibition. The mechanistic involvement of lipocalin-2 in aldosterone-stimulated MR expression and/or activation was further investigated. Collectively, the results demonstrate that lipocalin-2 plays a critical role in the cardiovascular damage induced by activation of the aldosterone-MR signaling axis.