Reduction in renal ACE2 expression in  subtotal nephrectomy in rats is  ameliorated with ACE inhibition.
Alterations within the RAS (renin-angiotensin system) are pivotal for the development of renal disease. ACE2 (angiotensin-converting enzyme 2) is expressed in the kidney and converts the vasoconstrictor AngII (angiotensin II) into Ang-(1-7), a peptide with vasodilatory and anti-fibrotic actions. Although the expression of ACE2 in the diabetic kidney has been well studied, little is known about its expression in non-diabetic renal disease. In the present study, we assessed ACE2 in rats with acute kidney injury induced by STNx (subtotal nephrectomy). STNx and Control rats received vehicle or ramipril (1 mg. kg (-1) of body weight . day (-1), and renal ACE, ACE2 and mas receptor gene and protein expression were measured 10 days later. STNx rats were characterized by polyuria, proteinuria, hypertension and elevated plasma ACE2 activity (all P<0.01) and plasma Ang-(1-7) (P<0.05) compared with Control rats. There was increased cortical ACE binding and medullary mas receptor expression (P<0.05), but reduced cortical and medullary ACE2 activity in the remnant kidney (P<0.05 and P<0.001 respectively) compared with Control rats. In STNx rats, ramipril reduced blood pressure (P<0.01), polyuria (P<0.05)and plasma ACE2 (P<0.01), increased plasma Ang-(1-7) (P<0.001), and inhibited renal ACE(P<0.001). Ramipril increased both cortical and medullary ACE2 activity (P<0.01), but reduced medullary mas receptor expression (P<0.05). In conclusion, our results show that ACE2 activity is reduced in kidney injury and that ACE inhibition produced beneficial effects in association with increased renal ACE2 activity. As ACE2 both degrades AngII and generates the vasodilator Ang-(1-7), a decrease in renal ACE2 activity, as observed in the present study, has the potential to contribute to the progression of kidney disease.
Velkoska
Elena
E
Department of Medicine, The University of Melbourne, Austin Health, Heidelberg 3081, Victoria, Australia.
Dean
Rachael G
RG
Burchill
Luke
L
Levidiotis
Vicki
V
Burrell
Louise M
LM
D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D005260:Female; D015870:Gene Expression; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D009392:Nephrectomy; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011141:Polyuria / Q000188:drug therapy / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D017257:Ramipril
Diabetes Care. 2006 Apr;29(4):848-52
16567826
Regul Pept. 2006 Dec 10;137(3):128-33
16934886
Regul Pept. 1998 Jun 30;74(2-3):177-84
9712179
Kidney Int. 2007 Sep;72(5):614-23
17579661
Circ Res. 2000 Sep 1;87(5):E1-9
10969042
Braz J Med Biol Res. 1992;25(6):651-4
1342241
Hypertension. 2003 Oct;42(4):574-9
12953014
Kidney Int. 2008 Dec;74(12):1610-6
19034303
Kidney Int. 2005 Nov;68(5):2189-96
16221218
J Biol Chem. 2000 Oct 27;275(43):33238-43
10924499
Nat Clin Pract Nephrol. 2009 Feb;5(2):89-100
19065132
Curr Opin Nephrol Hypertens. 2008 May;17(3):250-7
18408475
J Pathol. 2004 Dec;204(5):587-93
15538735
J Hypertens. 2000 Jun;18(6):749-55
10872560
Pflugers Arch. 2003 Nov;447(2):223-30
14534790
Physiol Rev. 1996 Apr;76(2):425-536
8618962
Eur Heart J. 2005 Feb;26(4):369-75; discussion 322-4
15671045
J Hepatol. 2007 Sep;47(3):387-95
17532087
Hypertension. 2004 May;43(5):1120-5
15078862
Hypertension. 2006 Mar;47(3):515-21
16365192
Hypertension. 1996 Apr;27(4):875-84
8613263
Hypertension. 1998 Sep;32(3):496-502
9740616
J Am Soc Nephrol. 2006 Nov;17(11):3067-75
17021266
Exp Physiol. 2008 May;93(5):685-93
18223027
Curr Pharm Des. 2007;13(26):2730-5
17897017
Semin Nephrol. 2001 Nov;21(6):554-62
11709803
Kidney Int. 1990 Jan;37(1):1-13
2137185
Diabetes. 2006 Jul;55(7):2132-9
16804085
Kidney Int. 2009 Jun;75(11):1184-1193
19262461
Am J Physiol Renal Physiol. 2005 Feb;288(2):F353-62
15467007
Hypertension. 2003 Mar;41(3):392-7
12623933
Exp Physiol. 2008 May;93(5):622-30
18223026
Hypertension. 2008 May;51(5):1312-7
18391097
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8258-63
12829792
Trends Endocrinol Metab. 2004 May-Jun;15(4):166-9
15109615
Kidney Int. 2001 Aug;60(2):715-21
11473654
Biochem J. 2004 Oct 1;383(Pt 1):45-51
15283675
Hypertension. 1995 Apr;25(4 Pt 2):663-73
7721413
Am J Physiol Renal Physiol. 2009 Feb;296(2):F398-405
19004932
JAMA. 2000 Jun 28;283(24):3177-9
10866846
Am J Kidney Dis. 2008 Apr;51(4):613-23
18371537
Clin Exp Pharmacol Physiol. 1984 Jul-Aug;11(4):431-5
6097381
Am J Pathol. 2006 Jun;168(6):1808-20
16723697
Am J Pathol. 2007 Aug;171(2):438-51
17600118
JAMA. 1980 Jul 25;244(4):346-9
6993700