Increased Urinary Angiotensin-Converting Enzyme 2 in Renal Transplant Patients with Diabetes

Fengxia Xiao,Swapnil Hiremath,Deepak Jadhav,Kajenny Srivaratharajah,Greg Knoll,Joseph Zimpelmann,Chris R J Kennedy,Kevin D Burns,Dean Fergusson,Michael Bader

doi:10.1371/journal.pone.0037649

Fengxia Xiao, Swapnil Hiremath + Show 8 more

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https://doi.org/10.1371/journal.pone.0037649

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Journal: PloS one	Publication Date: May 22, 2012
Citations: 68	License type: CC BY 4.0

Affiliation: University of Ottawa, Ottawa Hospital

Abstract

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n = 100) and healthy controls (age 45 yrs, 26% male, n = 50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p = 0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p = 0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients.

Highlights

Angiotensin-converting enzyme 2 (ACE2) is a recently identified member of the renin-angiotensin system (RAS) that degrades angiotensin (Ang) II to the seven amino acid peptide fragment Ang-(1-7) [1,2]
The principle objective of the present study was to determine if urinary ACE2 activity, protein, and mRNA can be detected in renal transplant patients, and to identify factors associated with the presence of ACE2
The major finding of this study is that urinary ACE2 activity and ACE2 protein are increased in kidney transplant recipients, compared to healthy control subjects, and the presence of diabetes strongly associates with urinary ACE2 levels in the patient population, by multivariate analysis

Summary

Introduction

Angiotensin-converting enzyme 2 (ACE2) is a recently identified member of the renin-angiotensin system (RAS) that degrades angiotensin (Ang) II to the seven amino acid peptide fragment Ang-(1-7) [1,2]. ACE2 is found in many tissues, expression is especially high in the kidney, within cells of the proximal tubule [3,4,5]. In mice deletion of the ACE2 gene is associated with development of late-stage glomerulosclerosis, and acceleration of diabetic nephropathy, in the absence of hypertension [6,7]. Administration of human recombinant ACE2 reduces blood pressure [8], and in diabetic mice, exogenous human ACE2 diminishes blood pressure and glomerular injury [9]. ACE2 may be an endogenous protector against the progression of chronic kidney disease (CKD)

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