Glomerular Localization and Expression of Angiotensin-Converting Enzyme 2 and Angiotensin-Converting Enzyme

Abstract

Angiotensin-converting enzyme 2 (ACE2) expression has been shown to be altered in renal tubules from diabetic mice. This study examined the localization of ACE and ACE2 within the glomerulus of kidneys from control (db/m) and diabetic (db/db) mice and the effect of chronic pharmacologic ACE2 inhibition. ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling. ACE, by contrast, was seen only in glomerular endothelial cells. By immunohistochemistry, in glomeruli from db/db mice, strong ACE staining was found more frequently than in control mice (db/db 64.6 ؎ 6.3 versus db/m 17.8 ؎ 3.4%; P < 0.005). By contrast, strong ACE2 staining in glomeruli from diabetic mice was less frequently seen than in controls (db/db 4.3 ؎ 2.4 versus db/m 30.6 ؎ 13.6%; P < 0.05). For investigation of the significance of reduced glomerular ACE2 expression, db/db mice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan, a specific angiotensin II type 1 receptor blocker. At the end of the study, glomerular staining for fibronectin, an extracellular matrix protein, was increased in both db/db and db/m mice that were treated with MLN-4760. Urinary albumin excretion (UAE) increased significantly in MLN-4760 -treated as compared with vehicle-treated db/db mice (743 ؎ 200 versus 247 ؎ 53.9 g albumin/mg creatinine, respectively; P < 0.05), and the concomitant administration of telmisartan completely prevented the increase in UAE associated with the ACE2 inhibitor (161 ؎ 56; P < 0.05). It is concluded that ACE2 is localized in the podocyte and that in db/db mice glomerular expression of ACE2 is reduced whereas glomerular ACE expression is increased. The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomerular injury.

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

“…The high expression of ACE2 in the normal kidney (2) and the reduced expression of ACE2 in diabetic rats (16) and human kidney diseases (17,18) suggest an ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2, most investigators have focused on ACE2 inhibition and demonstrated that ACE2 deficiency aggravated glomerular injury in mice (19)(20)(21). A recent study found that intraperitoneal injection of human recombinant ACE2 slowed the progression of diabetic nephropathy in diabetic mice, although exogenous proteins may cause immunity reaction after injection, which shortens its half-life (22).…”

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

“…However, inconsistencies can be found in mouse glomerular ACE2 presence as described even by the same group. 28,29 Besides, kinetic differences in AngI and AngII metabolism are shown to be exist between rat, human and sheep kidneys. 25,30,31 There are some limitations to our study.…”

Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy

“…Thus, Ang 1-7 has become a key component of the RAS system due to its beneficial effects in the cardiovascular system. Although the pathophysiological significance of ACE2 in renal injury remains to be established, emerging evidence suggests that ACE2 deficiency leads to increases in intrarenal Ang II levels (Ribeiro Oliveira Ferrario, 2006;Oudit et al;Wolf & Ritz, 2005;Ye et al;2006). Thus, recently ACE2 has also been proposed as an acute biomarker of renal disease, considering that upregulation of ACE2, and the subsequent increase in Ang 1-7 levels, may be a compensatory response to protect against tissue injury.…”