Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan

108

103

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the (5/6) nephrectomy ((5/6) Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or (5/6) Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG-(1-7) for 4 wk. In (5/6) Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In (5/6) Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. (5/6) Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in (5/6) Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with (5/6) Nx alone, an effect reversed by losartan. Treatment of (5/6) Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after (5/6) Nx. Inhibition of ACE2 in (5/6) Nx mice increases albuminuria via an AT(1) receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after (5/6) Nx. We propose that endogenous ACE2 is renoprotective in CKD.

Section: Discussionsupporting

confidence: 90%

Effect of ACE2 and angiotensin-(1–7) in a mouse model of early chronic kidney disease

Dilauro

Zimpelmann

Robertson

et al. 2010

108

103

“…In mice, expression of ACE2 in the tunica media of renal arterioles contrasts with the expression of ACE in the vascular endothelium of these arterioles (129). As first shown by us in the heart (68) and the aorta (65, 66), administration of an ANG II receptor antagonist leads to an increase kidney arteriole ACE2 gene expression (129). In keeping with previous studies (28), renal expression of ACE2 was reduced by kidney disease and subtotal nephrectomy (78).…”

supporting

confidence: 81%

“…ACE2 within the kidneys colocalizes with ACE in proximal and distal tubules and in podocytes within the glomerulus (87,133,156). In mice, expression of ACE2 in the tunica media of renal arterioles contrasts with the expression of ACE in the vascular endothelium of these arterioles (129). As first shown by us in the heart (68) and the aorta (65, 66), administration of an ANG II receptor antagonist leads to an increase kidney arteriole ACE2 gene expression (129).…”

mentioning

confidence: 92%

The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function

Ferrario

Varagić

2010

135

144

The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1-7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1-7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease.

“…In previous studies (43,47) it was found that ACE2 is increased in kidney cortex but decreased by immunostaining in glomeruli from young db/db mice (8 wk of age). In other models of diabetic kidney disease (Akita and in STZ-treated mice) kidney ACE2 protein or activity were also reported to be elevated in kidney cortex (33,35,40,43). In the present study, we measured ACE2 activity in both glomerular and tubular kidney isolates from older db/db mice (32 wk of age) and found that tubular ACE2 activity was increased compared with db/m controls.…”

Section: Discussionsupporting

confidence: 52%

Regulation of urinary ACE2 in diabetic mice

Wysocki

Garcia-Halpin

et al. 2013

Self Cite

118

Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10(-9) M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.