Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice - A renoprotective combination?

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.