Soluble ACE2 Is Filtered into the Urine. Issue 12 (29th December 2022)

• Record Type: Journal Article
• Authors: Nelson, Jonathan W.; Ortiz-Melo, David I.; Mattocks, Natalie K.; Emathinger, Jacqueline M.; Prescott, Jessica; Xu, Katherine; Griffiths, Robert C.; Wakasaki, Rumie; Piehowski, Paul D.; Hutchens, Michael P.; Coffman, Thomas M.; Gurley, Susan B.
• Is Part Of: Kidney360. Volume 3:Issue 12(2022)
• Page Start: 2086
• Page End: 2094
• Publication Date: 2022-12-29
• Subjects: hypertension -- ACE2 -- basic science -- kidney -- renin angiotensin system -- soluble ACE2; 616.61
• DOI: 10.34067/KID.0001622022
• Languages: English
• ISSNs: 2641-7650

Abstract

Key Points: Combining unique genetic and surgical models, we demonstrate that both renal and systemic sources contribute to angiotensin-converting enzyme 2 (ACE2) detected in the urine in angiotensin II–mediated hypertension. Micropuncture coupled with nanoproteomics confirm detection of ACE2 in early glomerular filtrate obtained from Bowman's capsule in mice. Kidney-derived ACE2 and soluble ACE2 may be useful clinical targets in kidney disease. Visual Abstract: Abstract : Background: ACE2 is a key enzyme in the renin-angiotensin system (RAS) capable of balancing the RAS by metabolizing angiotensin II (AngII). First described in cardiac tissue, abundance of ACE2 is highest in the kidney, and it is also expressed in several extrarenal tissues. Previously, we reported an association between enhanced susceptibility to hypertension and elevated renal AngII levels in global ACE2-knockout mice. Methods: To examine the effect of ACE2 expressed in the kidney, relative to extrarenal expression, on the development of hypertension, we used a kidney crosstransplantation strategy with ACE2-KO and WT mice. In this model, both native kidneys are removed and renal function is provided entirely by the transplanted kidney, such that four experimental groups with restricted ACE2 expression are generated: WT→WT (WT), KO→WT (KidneyKO), WT→KO (SystemicKO), and KO→KO (TotalKO). Additionally, we used nanoscale mass spectrometry–based proteomics to identify ACE2 fragments in early glomerular filtrate of mice. Results: Although significant differences in BP were not detected, a major finding of our study is that shed or soluble ACE2 (sACE2) was present in urine of KidneyKO mice that lack renal ACE2 expression. Detection of sACE2 in the urine of KidneyKO mice during AngII-mediated hypertension suggests that sACE2 originating from extrarenal tissues can reach the kidney and be excreted in urine. To confirm glomerular filtration of ACE2, we used micropuncture and nanoscale proteomics to detect peptides derived from ACE2 in the Bowman's space. Conclusions: Our findings suggest that both systemic and renal tissues may contribute to sACE2 in urine, identifying the kidney as a major site for ACE2 actions. Moreover, filtration of sACE2 into the lumen of the nephron may contribute to the pathophysiology of kidney diseases characterized by disruption of the glomerular filtration barrier.