Soluble ACE2 Is Filtered into the Urine.

Autor:	Nelson JW; Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon., Ortiz-Melo DI; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina., Mattocks NK; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina., Emathinger JM; Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon., Prescott J; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina., Xu K; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina., Griffiths RC; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina., Wakasaki R; Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon., Piehowski PD; Environmental and Biological Services Division, Pacific Northwest National Laboratory, Richland, Washington., Hutchens MP; Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon., Coffman TM; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina.; Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore., Gurley SB; Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.; Division of Nephrology, Department of Medicine, Duke University and Durham VA Health Care Centers, Durham, North Carolina.
Jazyk:	angličtina
Zdroj:	Kidney360 [Kidney360] 2022 Aug 09; Vol. 3 (12), pp. 2086-2094. Date of Electronic Publication: 2022 Aug 09 (Print Publication: 2022).
DOI:	10.34067/KID.0001622022
Abstrakt:	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. Competing Interests: T.M. Coffman reports serving in an advisory or leadership role for Cell Metabolism and The Journal of Clinical Investigation (editorial boards), Kidney Research Institute University of Washington, Singapore Eye Research Institute, and the Singapore Health Services (board of directors). S.B. Gurley serving as Associate Editor for the Diabetes and a family member being employed by, and having ownership interest in, United Therapeutics. M.P. Hutchens reports having ownership interest in ATT, Exxon, Frontier, and Verizon; and having patents or royalties with ProjectLite, LLC. P.D. Piehowski reports receiving research funding from Jacobs (worldwide research principal investigator) and Pfizer; and being employed by, and having patents or royalties with, Pacific Northwest National Laboratory. R. Wakasaki reports having ownership interest in Fuji Film Holdings, KDDI, Lion, and Toyota. All remaining authors have nothing to disclose. (Copyright © 2022 by the American Society of Nephrology.)
Databáze:	MEDLINE
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