Candesartan upregulates angiotensin‐converting enzyme 2 in kidneys of male animals by decreased ubiquitination

Abstract Candesartan is a common angiotensin‐II receptor‐1 blocker used for patients with cardiovascular and renal diseases. Angiotensin‐converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi‐organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2‐mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium‐hydrogen‐exchanger‐3 positive proximal‐convoluted‐tubules; ACE2‐ubiquitination was decreased by candesartan, accompanied with increased ubiquitin‐specific‐protease‐48 (USP48). In candesartan‐treated mouse renal proximal‐convoluted‐tubule cells, ACE2 abundances and activities were increased while ACE2‐ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex‐differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2‐ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan‐like‐drug choice in men and women prone to coronavirus infections.