The Effects of Aldosterone on Hypertension-Associated Kidney Injury in a Tg-hAS Mouse Model.

Abstract

Hypertension remains a global health challenge due to its high prevalence and association with premature morbidity and mortality. Aldosterone, a mineralocorticoid hormone, and its receptor, the mineralocorticoid receptor (MR), are highly implicated in hypertension pathogenesis. Aldosterone synthase is the sole enzyme responsible for producing aldosterone in humans. We established transgenic mice carrying the human aldosterone synthase gene (cyp11B2) and showed dramatically increased levels of aldosterone in female hemizygotes. High-salt diets persistently increased blood pressure in these mice, and salt-induced hypertension was significantly ameliorated by reducing aldosterone levels via an aldosterone synthase inhibitor or blocking MR via an MR inhibitor. Since both hypertension and hyperaldosteronism specifically induce chronic kidney disease, in this model, we demonstrated that chronic high-salt diets induced hypertension in this mouse line and resulted in kidney inflammation and injury. Both the aldosterone synthase inhibitor and the MR antagonist markedly blocked high-salt-diet-mediated kidney injury. Thus, this transgenic mouse line can be used to study the pathogenic mechanisms underlying aldosterone and its receptor and to screen therapeutic compounds for aldosterone-mediated hypertension and related complications, such as kidney disease, in humans.