Article

Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease.

Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Kidney International (impact factor: 6.61). 01/2009; 74(12):1610-6. DOI:10.1038/ki.2008.497 pp.1610-6
Source: PubMed

ABSTRACT Angiotensin converting enzyme (ACE) generates angiotensin II from angiotensin I, which plays a critical role in the pathophysiology of diabetic nephropathy. However, ACE2 generates angiotensin 1-7, which may protect the kidney by attenuating the effects of angiotensin II, since deletion of the Ace2 gene leads to glomerulosclerosis in mice, and pharmacologic inhibition of ACE2 exacerbates experimental diabetic nephropathy. We measured ACE2 and ACE expression in renal biopsies of patients with kidney disease due to type 2 diabetes to determine if the expression pattern is specific to diabetic nephropathy. ACE2 and ACE mRNA levels were measured by real-time PCR in laser microdissected renal biopsies from 13 diabetic and 8 control patients. ACE2 mRNA was significantly reduced by more than half in both the glomeruli and proximal tubules of the diabetic patients compared to controls, but ACE mRNA was increased in both compartments. There was a significant parallel decrease in ACE2 protein expression, determined by immunohistochemistry, in proximal tubules, a pattern not found in 12 patients with focal glomerulosclerosis or 10 patients with chronic allograft nephropathy. Our results suggest that the kidney disease of patients with type 2 diabetes is associated with a reduction in ACE2 gene and protein expression and this may contribute to the progression of renal injury.

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    Chapter: Renal Angiotensinogen Gene Expression and Tubular Atrophy in Diabetic Nephropathy
    Brice E. T. Nouthe, Maya Saleh, Shao-Ling Zhang, John S. D. Chan
    04/2012; , ISBN: 978-953-51-0543-5
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    Article: Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice.
    Renisha Nadarajah, Rosangela Milagres, Marc Dilauro, Alex Gutsol, Fengxia Xiao, Joseph Zimpelmann, Chris Kennedy, Jan Wysocki, Daniel Batlle, Kevin D Burns
    [show abstract] [hide abstract]
    ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1-7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy.
    Kidney International 04/2012; 82(3):292-303. · 6.61 Impact Factor
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    Article: Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes.
    Fengxia Xiao, Swapnil Hiremath, Greg Knoll, Joseph Zimpelmann, Kajenny Srivaratharajah, Deepak Jadhav, Dean Fergusson, Chris R J Kennedy, Kevin D Burns
    [show abstract] [hide abstract]
    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.
    PLoS ONE 01/2012; 7(5):e37649. · 4.09 Impact Factor

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Keywords

10 patients
 
12 patients
 
8 control patients
 
ACE expression
 
ACE mRNA levels
 
ACE2 mRNA
 
ACE2 protein expression
 
angiotensin II
 
chronic allograft nephropathy
 
critical role
 
diabetic nephropathy
 
diabetic patients
 
experimental diabetic nephropathy
 
expression pattern
 
focal glomerulosclerosis
 
kidney disease
 
pharmacologic inhibition
 
protein expression
 
real-time PCR
 
renal injury