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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. blood pressure; hypertension; renal function; renin; renal disease doi: 10.1152/ajprenal.00110.2010.

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.sub.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.sub.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. renin-angiotensin system; nephrectomy; albuminuria doi: 10.1152/ajprenal.00426.2009.

This study was performed to investigate the impact of acute hyperglycemia (HG) on the permeability of the normal glomerular filtration barrier in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was catheterized for urine collection, while simultaneously blood access was achieved. Rats received an intravenous (iv) infusion of either 1) hypertonic glucose to maintain blood glucose at 20-25 mM (G; n = 8); 2) hypertonic glucose as in 1) and a RhoA-kinase inhibitor (Y-27632; Rho-G; n = 8); 3) 20% mannitol (MANN; n = 7) or 4) hypertonic (12%) NaCl to maintain plasma crystalloid osmotic pressure ([[pi].sub.cry]) at ~320-325 mosmol/1 (NaCl; n = 8) or 5) physiological saline (SHAM; n = 8). FITC-Ficoll 70/400 was infused iv for at least 20 min before termination of the experiments, and plasma and urine were collected to determine the glomerular sieving coefficients ([theta]) for polydisperse Ficoll (molecular radius 15-80 [Angstrom]) by high-performance size-exclusion chromatography. In G there was a marked increase in [theta] for [Fico11.sub.55-80[Angstrom]] at 20 min, which was completely reversible within 60 min and abrogated by a Rho-kinase (ROCK) inhibitor, while glomerular permeability remained unchanged in MANN and NaC1. In conclusion, acute HG caused rapid, reversible increases in [theta] for large Ficolls, not related to the concomitant hyperosmolarity, but sensitive to ROCK inhibition. The changes observed were consistent with the formation of an increased number of large pores in the glomerular filter. The sensitivity of the permeability changes to ROCK inhibition strongly indicates that the cytoskeleton of the cells in the glomerular barrier may be involved in these alterations. microalbuminuria; RhoA-kinase; podocytes; endothelium; hyperosmolarity doi: 10.1152/ajprenal.00710.2009.

In rat diabetic animal models, ANG(1-7) treatment prevents the development of cardiovascular complications. Angiotensin-converting enzyme (ACE)2 is a major ANG(1-7)-generating enzyme in vascular smooth muscle cells (VSMCs), and its expression is decreased by a prolonged exposure to high glucose (HG), which is reflected by lower ANG(1-7) levels. However, the underlying mechanism of its downregulation is unknown and was the subject of this study. Rat aortic VSMCs were maintained in normal glucose (NG) or HG (~4.1 and ~23.1 mmol/l, respectively) for up to 72 h. Several PKC and NADPH oxidase inhibitors and short interfering (si)RNAs were used to determine the mechanism of HG-induced ACE2 downregulation. Cell lysates were subjected to Western blot analysis, real-time quantitative PCR, and ANG(1-7) radioimmunodetection. At 72 h of HG exposure, ACE2 mRNA, protein, and ANG(1-7) levels were decreased (0.17 [+ or -] 0.01-, 0.47 [+ or -] 0.03-, and 0.16 [+ or -] 0.01-fold, respectively), and the expression of NADPH oxidase subunit Noxl was increased (1.70 [+ or -] 0.2-fold). The HG-induced ACE2 decrease was reversed by antioxidants and Nox1 siRNA as well as by inhibitors of glycotoxin formation. ACE2 expression was PKC-[beta]II dependent, and PKC-[beta]II protein levels were reduced in the presence of HG (0.32 [+ or -] 0.03-fold); however, the PKC-[beta]II inhibitor CG-53353 prevented the HG-induced ACE2 loss and Nox1 induction, suggesting a nonspecific effect of the inhibitor. Our data suggest that glycotoxin-induced Noxl expression is regulated by conventional PKCs. ACE2 expression is PKC-[beta]II dependent. Nox1-derived superoxides reduce PKC-[beta]II expression, which lowers ACE2 mRNA and protein levels and consequently decreases ANG(1-7) formation. angiotensin-coverting enzyme 2/angiotensin-(1-7); NADPH oxidase; smooth muscle; vascular smooth muscle cells; glycotoxins; protein kinase C-[beta]II

In the current study, we investigated the expression and activity of ACE2 during pregnancy in normotensive and hypertensive rats, focusing on the relative contribution of the uterus and the placentas, the kidney serving as a reference. We used the Sabra rat model of salt-sensitive hypertension. We confirmed a systemic vasodilatory state during the third trimester of pregnancy, as evidenced by a reduction in blood pressure, both in normotensive and hypertensive rats. At the time that blood pressure was reduced, ACE2 was expressed abundantly in the reproductive organs. The relative levels of ACE2 mRNA in the pregnant animal were placenta > kidneys [greater than or equal to] uterus and of ACE2 activity kidney > placenta > uterus. In the uterus and the placenta, ACE2 expression was unaffected by strain, salt-loading, or the level of blood pressure. ACE2 activity in the uterus of the nonpregnant rat was not affected by any of these variables either, but during pregnancy increased in salt-loaded animals. When estimating the total contribution of the uterus to ACE2 mRNA and activity during pregnancy, we found that the amount of ACE2 mRNA increased in both strains irrespective of diet, but that ACE2 activity increased only in salt-loaded animals. We further estimated the relative total contribution of the uterus, placentas, and kidneys to ACE2 expression and activity during pregnancy by adjusting for mass and number of organs and found that the placentas were the major contributors, followed by the kidney and the uterus. We conclude that during pregnancy, the placentas, in particular, but also the uterus, constitute important sources of ACE2, in addition to its normal production in the kidney, leading to an estimated twofold increase in total ACE2 activity. These data are consistent the hypothesis that transient ACE2 overexpression and increased activity during pregnancy may be important in modulating systemic, as well as local hemodynamics in the uteroplacental unit. uterus; placenta; activity

Angiotensin converting enzyme (ACE) has been shown to be involved in regulation of apoptosis in nonintestinal tissues. This study examined the role of ACE in the modulation of intestinal adaptation utilizing ACE knockout mice ([ACE.sup.-/-]). A 60% small bowel resection (SBR) was used, since this model results in a significant increase in intestinal epithelial cell (EC) apoptosis as well as proliferation. Baseline villus height, crypt depth, and intestinal EC proliferation were higher, and EC apoptosis rates were lower in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. After SBR, EC apoptosis rates remained significantly lower in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. Furthermore, villus height and crypt depth after SBR continued to be higher in [ACE.sup.-/-] mice. The finding of a lower bax-to-bcl-2 protein ratio in [ACE.sup.-/-] mice may account for reduced EC apoptotic rates after SBR in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. The baseline higher rate of EC proliferation in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice may be due to an increase in the expression of several EC growth factor receptors. In conclusion, ACE appears to have an important role in the modulation of intestinal EC apoptosis and proliferation and suggests that the presence of ACE in the intestinal epithelium has a critical role in guiding epithelial cell adaptive response. short bowel syndrome; bax; bcl-2; intestine; adaptation

The factors inducing neutrophils to change angiotensin-converting enzyme (ACE) activity in cultured pulmonary endothelial cells were studied. It was observed that neutrophils mediate endothelial ACE dysfunction through factors that resemble those influencing cell lysis and augmented permeability. A model for the evaluation of neutrophil-mediated endothelial cell damage in the early stages was developed. It was concluded that polymorphonuclear leukocytes (PMN)-mediated ACE dysfunction may be caused by the synthesis of hydrogen peroxide by PMN, and its subsequent change to hydroxyl radicals.