Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Abstract

Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374 -F1384, 2012. First published February 29, 2012 doi:10.1152/ajprenal.00656.2011We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensinconverting enzyme 2 (ACE2) increased ninefold (P Ͻ 0.05) in DB females and threefold (P Ͻ 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68 ϩ cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (Ͼ75%, P Ͻ 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P Ͻ 0.05) and male (50%; P Ͻ 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58). Indeed, ACE2 inhibition or genetic knockout studies reveal a heightened sensitivity to ANG II-induced increases in blood pressure, as well as an exacerbation of end-organ damage in these experimental models (31,32,46,48,52,60). In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG I...

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

“…These results are in concordance with studies by Choi et al (9) who used an experimental unilateral ureteral obstruction mouse model. The increase in serum ACE2 activity in diabetes has been previously published (33,44,47,49). However, our study describes the effects of paricalcitol on ACE2 activity.…”

“…ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease, and various models of kidney injury (3,40,49,50). Our group has recently demonstrated that circulating and renal ACE2 is increased in NOD mice, and that enzyme expression was lowered by insulin treatment (33).…”

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

“…Typically, microliter amounts of serum or microgram quantities of tissue are required with this approach. We find that circulating ACE and ACE2 activities were significantly increased in a model of diabetic hypertension; however, ACE activity remained far higher than ACE2 which may contribute to the greater content of ANG II in diabetic mRen2.Lewis rats (148). Kinetic analysis using both labeled and unlabeled ANG II confirmed a sevenfold increase in the V max value for serum ACE2 in the female diabetic rat (148).…”

“…ACE2 is a membrane-bound monocarboxypeptidase (120 kDa) that converts ANG II directly to ANG-(1-7). Circulating levels of ACE2 are typically quite low particularly compared with ACE; however, serum ACE2 activity is elevated in diabetes, heart failure, and hypertension (41,136,148). ACE2 has a potentially significant role in the RAS pathway as a single catalytic step degrades ANG II but activates the ANG-(1-7) axis ( Fig.…”

“…In lieu of these approaches, the NH 2 -terminally intact forms of ANG II, ANG-(1-7), and ANG I are the predominant peptides identified in plasma and various tissues. Quantitation of the cell and urinary data reflects direct RIA-or ELISA-based methods (9,34,38,45,50,70,77,115,131,133,139,141,148).…”