Angiotensin‐II type 2 receptor activation modulates renal neprilysin and coronavirus receptor angiotensin converting enzyme‐2 expression and activity in obese rats fed high salt diet

Abstract

Neprilysin and coronavirus receptor angiotensin‐converting enzyme‐2 (ACE2) are peptidases critically involved in the breakdown of deleterious angiotensin‐II and the formation of protective angiotensin‐(1‐7). A disintegrin and metalloproteinase‐17 (ADAM17) is involved in the shedding of neprilysin and ACE2. We have reported the increase in renal angiotensin‐(1‐7) formation upon activation of angiotensin‐II type 2 receptor (AT2R). However, the modulation of expression and activity of these peptidases upon stimulation of AT2R in the kidney under the normal, obese, and high‐salt diet (HSD)‐fed condition is not known. Hence, we have treated, male, lean and obese Zucker rats (OZR) for 14 days without or with AT2R agonist C21 (1 mg/kg/day, via osmotic pumps) while fed HSD or normal diet. We have observed that the activity of neprilysin and ACE2 is decreased in the kidney of OZR fed either diet, however, only neprilysin activity has been found increased in the plasma (p<0.05). The C21‐treatment increased renal neprilysin expression and activity in the HSD‐fed OZR reflecting an increase in the urinary but decreased plasma activity (p<0.05). Likewise, The renal ACE2 expression is also increased upon C21‐treatment in HSD‐fed OZR and lean rats (p<0.05), but not the activity. These changes may be ascribed to ADAM17, as the renal expression of ADAM17 is paradoxically decreased upon HSD feeding in OZR (p<0.05) which is further reduced by C21‐treatment. Results indicate that AT2R activation differentially affects renal neprilysin and ACE2 which is critical in reference to current coronavirus pandemic.