Published Online
on April 12, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on December 19, 2003
Revised on February 6, 2004

Increased ACE 2 and Decreased ACE Protein in Renal Tubules From Diabetic Mice. A Renoprotective Combination?

Minghao Ye; Jan Wysocki; Parveen Naaz; Mohammad Reza Salabat; Michael S. LaPointe; and Daniel Batlle^*

From the Division of Nephrology and Hypertension (M.Y., J.W., P.N., M.R.S., M.S.L., D.B.), Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Ill, and VA Chicago Health Care System/Lakeside Division (M.S.L., D.B.), Chicago, Ill.

^* To whom correspondence should be addressed. E-mail: d-batlle{at}northwestern.edu.

Abstract--Unlike the ubiquitous angiotensin-converting enzyme (ACE), the ACE-related carboxypeptidase 2 (ACE 2) is predominantly expressed in the heart, kidney, and testis. ACE 2 degrades angiotensin (Ang) II to Ang (1-7) and Ang I to Ang (1-9). We investigated the expression of ACE and ACE 2 in a rodent model of type 2 diabetes. ACE and ACE 2 were measured in kidney and heart from 8-week-old no diabetic control (db/m) mice and diabetic (db/db) mice, which at this young age have obesity and hyperglycemia without nephropathy. In renal cortical tissue, ACE mRNA was reduced (db/db 0.31±0.06 versus db/m 0.99±0.05; P<0.005), whereas ACE 2 mRNA was not (db/db 0.94±0.05 versus db/m 1.03±0.11, NS). ACE protein was markedly reduced in kidney cortex of db/db mice (db/db 0.24±0.13 versus db/m 1.02±0.12; P<0.005), and this was associated with a corresponding decrease in renal ACE activity (db/db 12.7±3.7 versus db/m 61.6±4.4 mIU/mg protein; P<0.001). ACE 2 protein, by contrast, was increased in kidneys from diabetic mice (db/db 1.39±0.14 versus db/m 0.53±0.04; P<0.005). An increase in ACE 2 protein and a decrease in ACE protein, respectively, were also seen by immunostaining of renal cortical tubules from the db/db mice. In heart tissue, there were no significant differences between db/db and db/m mice in either ACE mRNA and protein or ACE 2 mRNA and protein. We conclude that in young db/db mice, ACE 2 protein in renal cortical tubules is increased, whereas ACE protein is decreased. We propose that the pattern of low ACE protein coupled with increased ACE 2 protein expression may be renoprotective in early stages of diabetes.

Key words: angiotensin-converting enzyme • renin-angiotensin system • diabetic nephropathy • obesity • mice • ACE-related carboxypeptidase 2

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