ACE2 Deficiency Protects Against Heme Protein-Induced Acute Kidney Injury.

Abstract

Angiotensin-converting enzyme 2 (ACE2) exerts countervailing effects on the renin-angiotensin aldosterone system. ACE2 also engages the spike protein of SARS-CoV-2. ACE2 protein has been shown recently to avidly bind heme. We examined the pathobiologic relevance of this heme-binding property of ACE2 by employing the glycerol-induced model of heme protein mediated AKI (HP-AKI) which is characterized by increased kidney heme content. We studied the response of ACE2-wildtype (ACE2^+/y) and ACE2-deficient (ACE2^-/y) mice to HP-AKI and quantitated kidney and cellular content of heme under relevant conditions. ACE2-deficient mice, compared with ACE2-wildtype mice, were significantly protected against HP-AKI as reflected by filtration markers, less histologic injury, and less expression of apoptosis and ferroptosis markers. ACE2-deficient mice also evinced lesser kidney heme content and a blunted induction of HO-1. HEK293 ACE2-overexpressing cells, compared with HEK293-native, when exposed to heme, retained higher amounts of heme. In HP-AKI, ACE2 expression and activity were reduced, and myoglobin and heme, administered independently, reduced ACE2 expression in the otherwise intact mouse kidney. Finally, with more severe HP-AKI, the protective effect of ACE2 deficiency was attenuated. We conclude that ACE2 deficiency confers protection against HP-AKI. We suggest that this reflects the recently recognized binding of heme to ACE2, such binding serving to facilitate renal entry of heme, a known nephrotoxin. These findings uncover a novel pathway of heme-dependent acute kidney injury. This is the first demonstration of the biologic relevance of chemical binding of heme by ACE2. Finally, we identify heme proteins and heme as novel determinants of ACE2 expression.