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.
Ye
Minghao
M
Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Ill 60611, USA.
Wysocki
Jan
J
Naaz
Parveen
P
Salabat
Mohammad Reza
MR
LaPointe
Michael S
MS
Batlle
Daniel
D
D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002268:Carboxypeptidases / Q000096:biosynthesis* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004790:Enzyme Induction; D007684:Kidney Tubules / Q000201:enzymology*; D008055:Lipids / Q000097:blood; D008168:Lung / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D009929:Organ Size; D009928:Organ Specificity; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000502:physiology
D001786:Blood Glucose; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2