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[Figure: see text].

Renin-angiotensin system as an important regulator of renal function has also a major role in inflammation. In the present study, the effects of captopril on renal dysfunction, renal cytokine levels, and renal tissue oxidative damage were investigated in lipopolysaccharide (LPS)-induced inflammation model in rats. Treatment of five groups of the rats was carried out as follows: (1) saline as a control, (2) LPS 1 mg/kg, and (3-5) 10, 50, or 100 mg/kg captopril 30 min, respectively, before LPS. The treatments were given for 12 days. Finally, the animals were deeply anesthetized, the blood samples were obtained, and the renal tissues were removed and kept for biochemical measurements. Administration of LPS increased serum blood urea nitrogen and creatinine (P < 0.001). Pretreatment with all doses of captopril decreased these parameters (P < 0.001). LPS also increased interleukin-6 (IL-6), malondialdehyde, and nitric oxide metabolites in the renal tissues (P<0.05 - P < 0.001), which was prevented by captopril (P < 0.05 - P < 0.001). The total thiol concentration and superoxide dismutase and catalase activities in the kidney of the LPS group were lower than the control (P < 0.001), while they were enhanced when the animals were cotreated by captopril (P <0.01 - P < 0.001). The results of the present study showed that captopril improved renal function and attenuated tissue oxidative stress in LPS-induced inflammation model in rats.

Chemical stimulation of the kidney increases sympathetic activity and blood pressure in rats. The hypothalamic paraventricular nucleus (PVN) is important in mediating the excitatory renal reflex (ERR). In this study, we examined the role of molecular signaling in the PVN in mediating the capsaicin-induced ERR and sympathetic activation. Bilateral PVN microinjections were performed in rats under anesthesia. The ERR was elicited by infusion of capsaicin into the cortico-medullary border of the right kidney. The reflex was evaluated as the capsaicin-induced changes in left renal sympathetic nerve activity and mean arterial pressure. Blockade of angiotensin type 1 receptors with losartan or inhibition of angiotensin-converting enzyme with captopril in the PVN abolished the capsaicin-induced ERR. Renal infusion of capsaicin significantly increased NAD(P)H oxidase activity and superoxide anion production in the PVN, which were prevented by ipsilateral renal denervation or microinjection of losartan into the PVN. Furthermore, either scavenging of superoxide anions or inhibition of NAD(P)H oxidase in the PVN abolished the capsaicin-induced ERR. We conclude that the ERR induced by renal infusion of capsaicin is mediated by angiotensin type 1 receptor-related NAD(P)H oxidase activation and superoxide anion production within the PVN.

The aim was to evaluate the effects and mechanisms of nebivolol on renal damage in Zucker diabetic fatty (ZDF) rats, in comparison with those of atenolol and captopril. Animals were divided into: control lean Zucker rats, ZDF rats, ZDF rats orally treated with nebivolol (10 mg/kg), atenolol (100 mg/kg) or captopril (40 mg/kg) for 6 months. Systolic blood pressure (SBP), blood glucose, kidney structure and function, plasma and kidney levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA), and oxidant status were evaluated. Kidney expressions of adenosine monophosphate-activated protein kinase (AMPK), NADPH oxidase (NOX) isoforms 2 and 4 and subunit p22 phox , nitric oxide synthase (NOS) isoforms, endothelial NOS (eNOS) uncoupling, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 were tested. All drugs induced a similar control of SBP. Nebivolol did not affect the increased plasma glucose. Unlike atenolol, nebivolol prevented the decrease in plasma insulin, and, like captopril, it reduced plasma lipid contents. Nebivolol ameliorated, to a greater extent than captopril, damages to renal structure and function, which were associated with an improvement in interlobular artery dysfunction. Nebivolol elevated kidney phosphorylation of AMPK, attenuated NOX4 and p22 phox expression and oxidative stress marker levels. Nebivolol increased plasma and renal NO, enhanced expressions of eNOS, p-eNOS and neuronal NOS, and suppressed eNOS uncoupling and inducible NOS expression. High ADMA in plasma and kidney were decreased by nebivolol through increasing DDAH2 and decreasing protein arginine N-methyltransferase 1. Long-term treatment of nebivolol ameliorated diabetic nephropathy, at least in part, via regulation of renal oxidative stress/NO pathway., (© 2018 John Wiley & Sons Australia, Ltd.)

Obstruction of urine flow at the level of the pelvo-ureteric junction (UPJO) and subsequent development of hydronephrosis is one of the most common congenital renal malformations. UPJO is associated with development of salt-sensitive hypertension, which is set by the obstructed kidney, and with a stimulated renin-angiotensin-aldosterone system (RAAS) in rodent models. This study aimed at investigating the hypothesis that 1) in pediatric patients with UPJO the RAAS is activated before surgical relief of the obstruction; 2) in rats with UPJO the RAAS activation is reflected by increased abundance of renal aldosterone-stimulated Na transporters; and 3) the injured UPJO kidney allows aberrant filtration of plasminogen, leading to proteolytic activation of the epithelial Na channel γ-subunit (γ-ENaC). Hydronephrosis resulting from UPJO in pediatric patients and rats was associated with increased urinary plasminogen-to-creatinine ratio. In pediatric patients, plasma renin, angiotensin II, urine and plasma aldosterone, and urine soluble prorenin receptor did not differ significantly before or after surgery, or compared with controls. Increased plasmin-to-plasminogen ratio was seen in UPJO rats. Intact γ-ENaC abundance was not changed in UPJO kidney, whereas low-molecular cleavage product abundance increased. The Na-Cl cotransporter displayed significantly lower abundance in the UPJO kidney compared with the nonobstructed contralateral kidney. The Na-K-ATPase α-subunit was unaltered. Treatment with an angiotensin-converting enzyme inhibitor (8 days, captopril) significantly lowered blood pressure in UPJO rats. It is concluded that the RAAS contributes to hypertension following partial obstruction of urine flow at the pelvo-ureteric junction with potential contribution from proteolytic activation of ENaC.

Many studies have shown that flavonoids are effective as antihypertensive drugs in arterial hypertension. In the present work, we have analyzed the effects of some flavonoid extracts in the spontaneous hypertensive rat model (SHR). An important feature of this study is that we have used a low dose, far from those that are usually applied in human therapy or experimental animals, a dose that responded to the criterion of a potential future commercial use in human subjects. Treatments were carried out for 6 and 12 weeks in two groups of SHR rats, which received apigenin, lemon extract, grapefruit + bitter orange (GBO) extracts, and cocoa extract. Captopril was used as a positive control in the SHR group treated for 6 weeks (SHR6) and Diosmin was used as the industry reference in the SHR group treated for 12 weeks (SHR12). Captopril and GBO extracts lowered the high arterial pressure of the SHR6 animals, but none of the extracts were effective in the SHR12 group. Apigenin, lemon extract (LE), GBO, and captopril also improved aortic vascular relaxation and increased plasma and urinary excretion of nitrites, but only in the SHR6 group. Kidney and urinary thiobarbituric acid reactive substances (TBARS) were also significantly reduced by GBO in the SHR6 rats. Apigenin also improved vascular relaxation in the SHR12 group and all the flavonoids studied reduced urinary thiobarbituric acid reactive substances (TBARS) excretion and proteinuria. Vascular abnormalities, such as lumen/wall ratio in heart arteries and thoracic aorta, were moderately improved by these treatments in the SHR6 group. In conclusion, the flavonoid-rich extracts included in this study, especially apigenin, LE and GBO improved vascular vasodilatory function of young adult SHRs but only the GBO-treated rats benefited from a reduction in blood pressure. These extracts may be used as functional food ingredients with a moderate therapeutic benefit, especially in the early phases of arterial hypertension., Competing Interests: The authors declare no conflict of interest.

Diazinon (Dz) is a widely used insecticide. It can induce nephrotoxicity and neurotoxicity via oxidative stress. Captopril, an angiotensin-converting enzyme inhibitor, is known for its antioxidant properties. In this study, we used captopril for ameliorating of Dz-induced kidney and brain toxicity in rats. Animals were divided into five groups as follows: negative control (olive oil), Dz (150 mg kg -1 ), captopril (60 and 100 mg kg -1 ) and positive control (N-acetylcysteine 200 mg kg -1 ) were injected intraperitoneally 30 min before Dz. After 24 h, animals were anesthetized and the brain and kidney tissues were separated. Then oxidative stress factors were evaluated. Also, blood was collected for assessment of blood urea nitrogen (BUN), creatinine (Cr) and nitric oxide (NO) levels. Dz significantly increased oxidative stress markers such as reactive oxygen species (ROS), lipid peroxidation, and protein carbonyl as well as glutathione (GSH) oxidation in both tissues. Increased levels of the BUN, Cr and NO were observed after Dz injection. Interestingly, captopril administration significantly decreased ROS production in both tissues. Captopril significantly protected kidney and brain against lipid peroxidation and GSH oxidation. Administration of captopril could markedly inhibit protein carbonyl production in kidney and brain after Dz injection. Furthermore, captopril ameliorated the increased level of BUN, Cr and NO. These results suggested that captopril can prevent Dz-induced oxidative stress, nephrotoxicity and neurotoxicity because of its antioxidant activity.

Aim: Angiotensin-converting enzyme inhibitors (ACEi) are widely used to deter the progression of chronic kidney disease (CKD). Besides controlling hypertension and reduction of intra-glomerular pressure, ACEi appear to have anti-fibrotic effects in the renal cortex. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an endogenous tetrapeptide that is degraded by ACE, has also been shown to ameliorate the pro-fibrotic phenotype displayed in CKD in our recent study. Whether the anti-fibrotic properties of ACEi are mediated by Ac-SDKP has not been fully investigated., Methods: To delineate the role of Ac-SDKP in ACE blockade, 12-week-old male BALB/c mice underwent sham operation or unilateral ureteric obstruction (UUO). UUO mice were subjected to: (i) vehicle; (ii) captopril or (iii) captopril in conjunction with S17092, a prolyl oligopeptidase inhibitor. After 7 days, mice were sacrificed and kidneys harvested for analyses., Results: After UUO, there were heightened expressions of collagen I, collagen III, fibronectin and α-SMA associated with significant levels of tubulointerstitial injury on histological examination. Furthermore, p44/42 mitogen-activated protein kinase (MAPK) and transforming growth factor beta 1(TGF-β1) signalling were upregulated. These were significantly ameliorated by captopril treatment alone but unaffected by co-administration of captopril with S17092. Captopril treatment had resulted in elevated urinary Ac-SDKP levels, an effect that was eliminated by the co-administration with S17092., Conclusion: This study allowed the investigation of the renoprotective property of ACEi in the absence of Ac-SDKP and proved conclusively that Ac-SDKP is the prime anti-fibrotic mediator of captopril, acting via p44/42 MAPK and TGF-β1 signalling pathways. Future research to expand CKD armamentarium should explore the utility of augmenting Ac-SDKP levels., (© 2017 Asian Pacific Society of Nephrology.)

Heart failure with preserved ejection fraction (HFpEF), a prevalent form of heart failure, is frequently accompanied by the metabolic syndrome and kidney disease. Because current treatment options of HFpEF are limited, evaluation of therapies in experimental models of HFpEF with the metabolic syndrome and kidney disease is needed. In this study, we evaluated the effects of captopril, furosemide, and their combination in aged, obese ZSF1 rats, an animal model of HFpEF with the metabolic syndrome and chronic kidney disease as comorbidities. Captopril (100 mg/kg), furosemide (50 mg/kg), or their combination was administered orally to obese ZSF1 rats aged 20 to 44 weeks. Untreated ZSF1 rats served as controls. After 24 weeks of treatment, captopril significantly lowered systemic blood pressure and attenuated HFpEF as evidenced by significantly reduced left ventricular end diastolic pressures (10.5 ± 1.4 vs. 4.9 ± 1.3 mm Hg in Control vs. Captopril, respectively) and significantly lower left ventricular relaxation time constants (28.1 ± 2.9 vs. 18.3 ± 3.1 ms in Control vs. Captopril, respectively). The captopril-induced improvement in left ventricular function was associated with reduced cardiac hypertrophy, ischemia, necrosis, and vasculitis. Captopril also increased renal blood flow and glomerular filtration rate, reduced renal vascular resistance and proteinuria, and improved renal histology (ie, reduced renal hypertrophy, glomerulosclerosis, and tubular atrophy/dilation). Furosemide alone provided little benefit; moreover, furosemide did not augment the therapeutic benefits of captopril. This study suggests that chronic administration of captopril, but not furosemide, could be beneficial in patients with HFpEF, particularly in those with comorbidities such as obesity, diabetes, and dyslipidemias.

The authors evaluated the effectiveness of percutaneous renal revascularization (PRR) with stenting for the treatment of atherosclerotic renal artery stenosis (ARAS) in patients with coronary artery disease and the usefulness of captopril renal scintigraphy for predicting clinical outcomes after PRR. Sixty-four consecutive patients, referred for evaluation of suspected ARAS, after coronary angiography, underwent baseline captopril renal scintigraphy followed by renal angiography. Forty-four patients (68.7%) were diagnosed with a significant ARAS≥ 60% and were treated with PRR plus medical therapy. Twenty-four months after PRR, 86.4% and 73.3% of patients showed a hypertension and renal benefit, respectively. Captopril renal scintigraphy positivity had moderate sensitivity and high specificity in predicting a hypertension and renal benefit. In patients with ARAS≥ 70%, the sensitivity and specificity were 100% for both a hypertension and renal benefit.PRR for ARAS conferred a substantial benefit in patients with a high coronary artery disease burden. Captopril renal scintigraphy was highly accurate in predicting clinical outcomes., (©2018 Wiley Periodicals, Inc.)

Renal innervation operates in conjunction with the intrarenal renin-angiotensin system (RAS) to control tubular reabsorption of sodium and water. This relationship remains unexplored in diabetic nephropathy. This study investigates the effects of acute RAS inhibition and chronic renal denervation on renal function in diabetic rats. Diabetes was induced in mRen-2 rats prior to conducting chronic bilateral denervation in diabetic and normoglycaemic animals. At 12-weeks post-diabetic induction, renal haemodynamics and tubular handling of sodium and water were measured before and after acute captopril infusion. Neither GFR nor renal blood flow were affected by diabetes or chronic renal denervation alone. While captopril produced natriuretic and diuretic responses in chronically-denervated diabetic animals, shown by increases (P<0.05) of 38±14% in absolute (U Na V), and 71±20% in fractional sodium excretion (FE Na ), and 68±17% in urine volume (UV); in the innervated-diabetic group captopril produced anti-natriuretic effects (U Na V and FE Na reduced by 41±10% and 29±13%, respectively; all P<0.05). This difference was not observed however in normoglycaemic groups where RAS inhibition produced anti-natriuretic (normoglycaemic denervated vs. innervated: 56±14% vs. 49±14% U Na V; 45±13% vs. 37±14% FE Na ) and anti-diuretic (normoglycaemic-denervated vs. innervated: 34±8% vs. 38±10% UV) effects in both denervated and innervated animals. These data indicate that renal neuronal control is altered in chronic hyperglycaemia. The role of the RAS in sodium conservation in the diabetic kidney, appears to be more significant in the absence of renal innervation, suggesting that the interaction between the RAS and renal sympathetic nervous system is responsible for changes in renal function in diabetic nephropathy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This study has examined the role of supplementing a treatment of diabetic rats with captopril (CAP), metformin (MET) or CAP-MET with the antioxidant amino acid taurine (TAU) on biochemical indices of diabetes-induced metabolic changes, oxidative stress and nephropathy. To this end, groups of 6 male Sprague-Dawley rats (250-375 g) were made diabetic with a single, 60 mg/kg, intraperitoneal dose of streptozotocin (STZ) in 10 mM citrate buffer pH 4.5 and, after 14 days, treated daily for up to 42 days with either a single oral dose of CAP (0.15 mM/kg), MET (2.4 mM/kg) or TAU (2.4 mM/kg), or with a binary or tertiary combination of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. All rats were sacrificed by decapitation on day 57 and their blood and kidneys collected. In addition, a 24 h urine sample was collected starting on day 56. Compared to normal rats, untreated diabetic ones exhibited frank hyperglycemia (+313%), hypoinsulinemia (-76%) and elevation of the glycated hemoglobin value (HbA 1c , +207%). Also they showed increased plasma levels of Na + (+35%), K + (+56%), creatinine (+232%), urea nitrogen (+158%), total protein (-53%) and transforming growth factor-β1 (TGF-β1, 12.4-fold) values. These changes were accompanied by increases in the renal levels of malondialdehyde (MDA, +42%), by decreases in the renal glutathione redox state (-71%), and activities of catalase (-70%), glutathione peroxidase (-71%) and superoxide dismutase (-85%), and by moderate decreases of the urine Na + (-33%) and K + (-39%) values. Following monotherapy, MET generally showed a greater attenuating effect than CAP or TAU on the changes in circulating glucose, insulin and HbA 1c levels, urine total protein, and renal SOD activity; and CAP appeared more potent than TAU and MET, in that order, in antagonizing the changes in plasma creatinine and urea nitrogen levels. On the other hand, TAU generally provided a greater protection against changes in glutathione redox state and in CAT and GPx activities, with other actions falling in potency between those of CAP and MET. Adding TAU to a treatment with CAP, but not to one with MET, led to an increase in protective action relative to a treatment with drug alone. On the other hand, the actions of CAP-MET, which were about equipotent with those of MET, became enhanced in the presence of TAU, particularly against the changes of the glutathione redox state and activities of antioxidant enzymes. In short, the present results suggest that the addition of TAU to a treatment of diabetes with CAP or CAP-MET, and sometimes to one with MET, will lead to a gain in protective potency against changes in indices of glucose metabolism and of renal functional impairment and oxidative stress.

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis., Competing Interests: Drs. Imig and Falck have a patent application that covers the composition of matter for EET-A. There are no other conflicts of interest, financial or otherwise, are declared by the authors., (© 2016 Authors; published by Portland Press Limited.)

Vasoactive agents are used in critical care to optimize circulatory function, but their effects on renal tissue oxygenation in the absence of anesthesia remain largely unknown. Therefore, we assessed the effects of multiple vasoactive agents on regional kidney oxygenation in awake sheep. Sheep were surgically instrumented with pulmonary and renal artery flow probes, and combination fiber-optic probes, in the renal cortex and medulla, comprising a fluorescence optode to measure tissue Po2 and a laser-Doppler probe to assess tissue perfusion. Carotid arterial and renal venous cannulas enabled measurement of arterial pressure and total renal oxygen delivery and consumption. Norepinephrine (0.1 or 0.8 μg·kg(-1)·min(-1)) dose-dependently reduced cortical and medullary laser Doppler flux (LDF) and Po2 without significantly altering renal blood flow (RBF), or renal oxygen delivery or consumption. Angiotensin II (9.8 ± 2.1 μg/h) reduced RBF by 21%, renal oxygen delivery by 28%, oxygen consumption by 18%, and medullary Po2 by 38%, but did not significantly alter cortical Po2 or cortical or medullary LDF. Arginine vasopressin (3.3 ± 0.5 μg/h) caused similar decreases in RBF and renal oxygen delivery, but did not significantly alter renal oxygen consumption or cortical or medullary LDF or Po2. Captopril had no observable effects on cortical or medullary LDF or Po2, at a dose that increased renal oxygen delivery by 24%, but did not significantly alter renal oxygen consumption. We conclude that vasoactive agents have diverse effects on regional kidney oxygenation in awake sheep that are not predictable from their effects on LDF, RBF, or total renal oxygen delivery and consumption., (Copyright © 2015 the American Physiological Society.)

Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy.

Our recent publication showed that a small bioactive pigment epithelium derived factor (PEDF) peptide (P78-PEDF) prevents the development of diabetic nephropathy (DN). However, its effects on the progression of established DN were not clear. Therefore, the purpose of this study was to determine the effect of P78-PEDF in the progression of DN and to compare the effects of P78-PEDF and an ACE inhibitor (ACEi), a standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with P78-PEDF or captopril starting at 6 wks of age for 12 wks (early treatment) or starting at 12 wks of age for 6 wks (late treatment). We first established the optimal dose of the P78-PEDF peptide to ameliorate DN in Ins2(Akita) mouse for a 6 wk study period and found that the peptide was effective at 0.1- 0.5 µg/g/day. We next showed that early or late treatment with P78-PEDF resulted in protection from DN as indicated by reduced albuminuria, kidney macrophage recruitment, histological changes, inflammatory cytokines and fibrotic markers (kidney TNF-α, fibronectin, VEGFA and EGFR), and restored nephrin expression compared with vehicle-treated Ins2(Akita) mice. Interestingly, only early but not late treatment with captopril was as effective as P78-PEDF in reducing most DN complications, despite its lack of effect on nephrin, VEGFA and EGFR expression. These findings highlight the importance of P78-PEDF peptide as a potential therapeutic modality in both the development and progression of diabetic renal injury.

Ischemia and subsequent reperfusion are known to impair renal function. We examined several agents that might prevent renal impairment or enhance the recovery of renal function after ischemia/reperfusion injury in rats. Different degrees of preventive effects were observed in rats treated with captopril, BQ-123 (endothelin type A receptor antagonist), sodium nitroprusside (SNP, a nitric oxide donor), and losartan (angiotensin II type 1 receptor antagonist). Only minimal changes in renal morphology were observed after treatment with losartan, SNP, captopril, and BQ-123 compared with control animals. On the other hand, lesions were prominent in the N(G)-nitro-L-arginine-methyl ester (L-NAME)- and L-arginine-treated rats. The Na(+)-K(+) ATPase activity of ischemic kidneys was, however, preserved in all treatment groups, except in those treated with L-arginine and L-NAME, which showed a marked reduction in Na(+)-K(+) ATPase activity. Our post-treatment data suggest that losartan and SNP have the greatest potential for therapeutic use to mitigate post-ischemic renal damage and functional impairment.

Purpose: Limited studies have shown antifibrotic effects of pentoxifylline, captopril, simvastatin, and tamoxifen. No comparisons are available of the effects of these drugs on prevention of renal and bladder changes in partial urethral obstruction (PUO)., Materials and Methods: The rats were divided into six groups (n=7). The sham-operated rats (group I) only underwent laparotomy and did not receive any treatments. The PUO groups (group II-VI) received normal saline (PUO+NS), pentoxifylline (100 mg/kg/d; PUO+PEN), captopril (35 mg/kg/d; PUO+CAP), simvastatin (15 mg/kg/d; PUO+SIM), or tamoxifen (10 mg/kg/d; PUO+TAM) by gavage for 28 days. Then, the volume and/or length of the kidney components (tubules, vessels, and fibrous tissue) and the bladder components (epithelial and muscular layers, fibrous tissue, fibroblast and fibrocyte number) were quantitatively evaluated on the microscopic sections by use of stereological techniques., Results: The volume of renal and bladder fibrosis was significantly ameliorated in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. Also, the volume and length of the renal tubules and vessels and bladder layers were more significantly protected in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups., Conclusions: Treatment of PUO with PEN was more effective in the prevention of renal and bladder fibrosis and in the preservation of renal and bladder structures.

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p<0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p<0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p<0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

Imaging of the kidney using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) presents a major opportunity to examine differences in tissue oxygenation within the cortex and medulla applicable to human disease. The aim of this study was to evaluate BOLD signals before and after treatment with RAS inhibitors in hypertensive chronic kidney disease (CKD) patients. Ten patients with stable CKD and 5 healthy volunteers were included. Five CKD patients were subjected to BOLD MRI scan before and after chronic treatment with 300 mg/day aliskiren for at least 6 weeks. Five other CKD patients received BOLD MRI before and 1 hour after acute treatment with 50 mg captopril. A group of healthy volunteers (n=5) was scanned before and 1 hour after acute treatment with 50 mg captopril. The 10 patients had a mean age of 61±17 years; eGFR of 30±11 mL/min per 1.73 m(2) . Office systolic and diastolic blood pressures when on a RAS inhibito, were 130±10 and 86±5 mmHg in CKD patients. Control subjects had normal kidney function and were not on any medication. In untreated condition, systolic and diastolic arterial blood pressure elevated, 145±6 and 95±4 mmHg, respectively. After chronic treatment with aliskiren, arterial blood pressure decreased in all patients in this group, 127±3 mmHg and 77±3 mmHg. After acute treatment with captopril arterial blood pressure reduced to 125±4 and 71±8 mmHg. Tissue intensity signal (T2*) was increased in medulla after chronic treatment from 29±6 to 34±6 and after acute treatment with captopril from 34±9 to 38±11 in CKD patients. In addition, T2* ratio between cortex and medulla decreased in CKD patients after chronic treatment and acute treatment. This ratio remained stable in healthy volunteers before and after treatment with captopril 1.62±0.1 and 1.65±0.1, respectively. This study shows for the first time that RAS inhibitors change BOLD signal in CKD patients. Importantly, in healthy volunteers, a RAS inhibitor had no such effect. Further investigation is required., (©2014 Wiley Periodicals, Inc.)

Background: Dioscorea opposita Thunb. (Huai Shan Yao, DOT), a common staple food in China, has been used for more than 2000 years in traditional Chinese medicine (TCM) to treat different systemic diseases including hypertension. The objective of this study was to investigate the possible antihypertensive effects of the aqueous extract of (DOT) in renovascular hypertensive rats as well as the mechanism in reducing blood pressure., Methods: The two-kidney one-clip (2K1C) Goldblatt model of renovascular hypertension was used in Wistar rats. Rats with captopril, low-dose DOT and high-dose DOT treated 2K1C groups for 6 weeks. The blood pressure, cardiac mass index (heart weight/body weight), plasma level of angiotensin-II (Ang-II), endothelin-1(ET-1), superoxide dismutase (SOD) and malondialdehyde (MDA) were evaluated., Results: DOT significantly reduced mean systolic and diastolic blood pressure after treatment. DOT also significantly increased plasma SOD activity but decreased plasma MDA concentration. Renal function was improved with captopril and DOT. DOT reduced plasma Ang-II activity and plasma ET concentration. They couldalso significantly reduce the left ventricular hypertrophy and cardiac mass index., Conclusions: Our results suggest that DOT may have an antihypertensive effect on hypertension by inhibit ET-converting enzyme and antioxidant activity, which warrant further exploration.

Angiotensin II type 2 receptor (AT2R)-mediated vasodilation has been demonstrated in different vascular beds in vitro and in perfused organs. In vivo studies, however, consistently failed to disclose renal vasodilator responses to compound 21, a selective AT2R agonist, even after angiotensin II type 1 receptor blockade. Here, we investigated in vivo whether angiotensin-converting enzyme inhibition, reducing endogenous angiotensin II levels, could unmask the effects of selective AT2R stimulation on blood pressure and renal hemodynamics in normotensive and hypertensive rats. After pretreatment with the angiotensin-converting enzyme inhibitor captopril, intravenous administration of compound 21 did not affect blood pressure and induced dose-dependent renal vasodilator responses in spontaneously hypertensive but not in normotensive rats. The D1 receptor agonist fenoldopam, used as positive control, reduced blood pressure and renal vascular resistance in both strains. The AT2R antagonist PD123319 and the nitric oxide synthase inhibitor L-NMMA (N(G)-monomethyl-L-arginine acetate) abolished the renal vasodilator response to compound 21 without affecting responses to fenoldopam. The cyclooxygenase inhibitor indomethacin partially inhibited the renal vascular response to compound 21, whereas the bradykinin B2 receptor antagonist icatibant was without effect. Angiotensin-converting enzyme inhibition unmasked a renal vasodilator response to selective AT2R stimulation in vivo, mediated by nitric oxide and partially by prostaglandins. AT2R may have a pathophysiological role to modulate renal hemodynamic effects of angiotensin II in the hypertensive state.

The renin-angiotensin-aldosterone system (RAAS) regulates BP and salt-volume homeostasis. Juxtaglomerular (JG) cells synthesize and release renin, which is the first and rate-limiting step in the RAAS. Intense pathologic stresses cause a dramatic increase in the number of renin-producing cells in the kidney, termed JG cell recruitment, but how this occurs is not fully understood. Here, we isolated renal CD44(+) mesenchymal stem cell (MSC)-like cells and found that they differentiated into JG-like renin-expressing cells both in vitro and in vivo. Sodium depletion and captopril led to activation and differentiation of these cells into renin-expressing cells in the adult kidney. In summary, CD44(+) MSC-like cells exist in the adult kidney and can differentiate into JG-like renin-producing cells under conditions that promote JG cell recruitment.

Objectives: To investigate the potential protective effects of captopril, the angiotensin-converting enzyme inhibitor, in diabetic rats exposed to ischaemia/reperfusion (I/R) renal injury., Methods: Following successful induction of diabetes, captopril treatment (50 mg/kg/day, p.o.) was applied for 4 weeks, after which bilateral renal ischaemia was induced for 30 min followed by reperfusion for 24 h., Results: Captopril significantly attenuated hyperglycaemia and hypoinsulinaemia in diabetic rats, and significantly reduced the elevations of serum creatinine and aldosterone levels, and renal malondialdehyde, tumour necrosis factor-α and nitric oxide (NO), and prevented the depletion of reduced glutathione caused by I/R in diabetic rats. Histopathological renal tissue damage induced by I/R in diabetic rats was ameliorated by captopril treatment. Immunohistochemical analysis revealed that captopril significantly attenuated the reduction of insulin content in pancreatic islet β-cells, and decreased the I/R-induced expression of inducible NO synthase, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin and heme oxygenase-1 in the kidney tissue of diabetic rats., Conclusions: Captopril represents a potential candidate to reduce the risk of renal injury induced by ischaemia/reperfusion in type 2 diabetes., (© 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society.)

This study deals with changes, induced by hypertension and its treatment, in the function and properties of mitochondria in the heart and kidneys. Male, 16-week-old hypertensive rats were allocated to 3 groups: (i) animals treated daily for 4 weeks with captopril (CAP, 80 mg·(kg body mass)(-1), n = 45), (ii) animals treated with CAP + nifedipine (NIF, 10 mg·kg(-1), n = 45), or (iii) untreated hypertensive controls (n = 96). Wistar rats (n = 96) were used as normotensive controls. Systolic blood pressure (SBP), heart rate (HR), and heart mass / body mass (HW/BW) ratio were measured at the beginning and end of the experiments; measurements for mitochondrial Mg(2+)-ATPase activity, O(2)-consumption (QO(2)), respiratory control index (RCI), ADP/O, oxidative phosphorylation rate (OPR), conjugated diene content (CD), and membrane fluidity (MF) were also taken at different time intervals. In the heart, elevated SBP, HR, and HW/BW accompanied increased QO(2), OPR, and Mg(2+)-ATPase activity, indicating an adaptive response to hypertension-induced increase in the energy demands of the myocardium. Treatments with CAP or with CAP + NIF were very similar in their prevention of increase in SBP, HR, HW/BW, and the rise in OPR (all p < 0.05-0.01). In the kidneys, hypertension induced a drop in OPR; however, antihypertensive therapy aggravated the resulting energy deficiency, whereby treatment with CAP + NIF was more detrimental than treatment with CAP alone. Heart and kidney mitochondria exhibited negligible changes in CD and moderately increased MF, which was more potentiated by treatment with CAP alone than with CAP + NIF.

Objective: The association between renal hypoxia and the development of renal injury is well established. However, no adequate method currently exists to non-invasively measure functional changes in renal oxygenation in normal and injured patients., Method: R2* quantification was performed using renal blood oxygen level-dependent properties. Five healthy normotensive women (50 ± 5.3 years) underwent magnetic resonance imaging in a 1.5T Signa Excite HDx scanner (GE Healthcare, Waukesha, WI). A multiple fast gradient-echo sequence was used to acquire R2*/T2* images (sixteen echoes from 2.1 ms/slice to 49.6 ms/slice in a single breath hold per location). The images were post-processed to generate R2* maps for quantification. Data were recorded before and at 30 minutes after the oral administration of an angiotensin II-converting enzyme inhibitor (captopril, 25 mg). The results were compared using an ANOVA for repeated measurements (mean + standard deviation) followed by the Tukey test. ClinicalTrials.gov: NCT01545479., Results: A significant difference (p<0.001) in renal oxygenation (R2*) was observed in the cortex and medulla before and after captopril administration: right kidney, cortex = 11.08 ± 0.56 ms, medulla = 17.21 ± 1.47 ms and cortex = 10.30 ± 0.44 ms, medulla = 16.06 ± 1.74 ms, respectively; and left kidney, cortex= 11.79 ± 1.85 ms, medulla = 17.03 ± 0.88 ms and cortex = 10.89 ± 0.91 ms, medulla = 16.43 ± 1.49 ms, respectively., Conclusions: This result suggests that the technique efficiently measured alterations in renal blood oxygenation after angiotensin II-converting enzyme inhibition and that it may provide a new strategy for identifying the early stages of renal disease and perhaps new therapeutic targets.

Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.

Effect of captopril treatment on capability of heart and kidney mitochondria to produce ATP was investigated in spontaneously hypertensive rats (SHR). Heart mitochondria from SHR responded to hypertension with tendency to compensate the elevated energy demands of cardiac cells by moderate increase in mitochondrial Mg2+-ATPase activity, membrane fluidity (MF) and in majority of functional parameters of the mitochondria (p>0.05). Significant increase exhibited only the oxygen consumption (QO2; p<0.01-0.001) and oxidative phosphorylation rate (OPR; p<0.003) with glutamate+malate (GLUT+MAL) as substrates. Lowering the blood pressure (p<0.02) captopril also eliminated the above compensatory response and impaired the oxidative ATP production by decreasing OPR (p<0.001). Kidney mitochondria of SHR experienced serious disarrangement in parameters of oxidative ATP production: increase in Mg2+-ATPase activity (p<0.05) but, also scattered QO2 values (p<0.03-0.01) leading to decrease in OPR and the ADP:O (p<0.05-0.01) values with both GLUT+MAL and succinate as substrates. Captopril treatment does not alleviated but even worsened the above alterations. Mg2+-ATPase became also decreased and the depression of ADP:O became aggravated (p<0.0001).

Renin, an aspartyl protease that catalyzes the rate-limiting step in the renin-angiotensin system (RAS), is proteolytically activated by a second protease [referred to as the prorenin processing enzyme (PPE)] before its secretion from the juxtaglomerular cells of the kidney. Although several enzymes are capable of activating renin in vitro, the leading candidate for the PPE in the kidney is cathepsin B (CTSB) due to is colocalization with the renin precursor (prorenin) in juxtaglomerular cell granules and because of its site-selective activation of human prorenin both in vitro and in transfected tissue culture cell models. To verify the role of CTSB in prorenin processing in vivo, we tested the ability of CTSB-deficient (CTSB-/-) mice to generate active renin. CTSB-/- mice do not exhibit any overt symptoms (renal malformation, preweaning mortality) typical of an RAS deficiency and have normal levels of circulating active renin, which, like those in control animals, rise more than 15-fold in response to pharmacologic inhibition of the RAS. The mature renin enzyme detected in kidney lysates of CTSB-/- mice migrates at the same apparent molecular weight as that in control mice, and the processing to active renin is not affected by chloroquine treatment of the animals. Finally, the distribution and morphology of renin-producing cells in the kidney is normal in CTSB-/- mice. In conclusion, CTSB-deficient mice exhibit no differences compared with controls in their ability to generate active renin, and our results do not support CTSB as the PPE in mice.

Hydronephrotic kidney with a differential renal function greater than 55% is defined as supranormal. The signification of this finding remains controversial. In this article, the authors reported a case of supranormal function in obstructive hydronephrosis. Differential renal functions were evaluated after administration of captopril and after pyeloplasty. The role of captopril renography as a prognostic factor for surgery is discussed., (Copyright 2009 Elsevier España, S.L. y SEMNIM. All rights reserved.)

Doxorubicin (Dox) is a potent anticancer agent; its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study investigated the possible protective effect of telmisartan, an angiotensin AT(1)-receptor blocker versus captopril, an angiotensin-converting enzyme inhibitor, on Dox-induced cardiotoxicity and nephrotoxicity in rats. Rats were allocated into four groups. Control group, Dox group, Dox+telmisartan group, and Dox+captopril group. Cardiotoxicity and nephrotoxicity were assessed biochemically and histopathologically. Frozen heart and kidney specimens were used for estimation of lipid peroxides product (MDA), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO). Expression of induced nitric oxide synthase (iNOS) was detected by immunohistochemistry. Coadministration of either telmisartan or captopril with Dox equally decreased the biochemical markers of both cardiotoxicity (LDH and CK-MP) and nephrotoxicity (urea and creatinine). Both telmisartan and captopril attenuated the effects of Dox on oxidative stress parameters and NO. Histopathologically, coadministration of either drug with Dox was able to attenuate Dox-induced myocardial fibrosis and renal tubular damage. Immunohistochemistry, expression of iNOS was increased in both cardiac and renal tissues. Both telmisartan and captopril significantly and equally attenuated the effect of Dox on all measured parameters. These results suggested that telmisartan has protective effects equal to that of captopril against Dox-induced cardiotoxicity and nephrotoxicity; implying that angiotensin II pathway plays a role in Dox-induced cardiac and renal damage. The protective effect of either drug relies, at least in part, on their antioxidant effects and decreased the expression of iNOS.

Recent studies indicated pulse pressure as a risk factor for left ventricular hypertrophy, myocardial infarction, congestive heart failure and stroke as well as chronic renal failure progression. The present study examined the effects of carvedilol and its combination with captopril on blood pressure, left ventricular hypertrophy, kidney vascular changes and kidney function in spontaneously hypertensive rats with adriamycin nephropathy. Four groups of 20 SHR each were involved: (1) control group: SHR; (2) ADR group: SHR treated with ADR (2mg/kg i.v. twice in 20 days); (3) ADR-C group: SHR treated with ADR and carvedilol (30 mg/kg/day) and (4) ADR-CC group: SHR treated with ADR and carvedilol (30 mg/kg/day) and captopril (60 mg/kg/day). Systolic-, diastolic- and mean-pressures and pulse pressure were determined at weeks 6 and 12 after the second ADR injection; and body weight, creatinine clearance and proteinuria at weeks -3, 6 and 12. The rats were sacrificed at week 6 or 12, the weights of the left and right ventricles and kidneys measured and the kidney vascular index was calculated as described by Bader and Mayer. Both carvedilol alone and combined with captopril significantly reduced systemic blood pressure but the effect of the latter was more pronounced and registered from week 4 till the end of the study. Carvedilol and its combination with captopril significantly decreased SBP, DBP and MAP. They also decreased PP, prevented the development of LVH, and renal vascular changes and slowed the progression of chronic renal failure and these effects were stronger in the ADR-CC group than in the ADR-C group. The antihypertensive drugs failed to prevent proteinuria in ADR SHR. Significant positive correlations were found between PP (but not SBP, DBP and MAP) and both proteinuria and Ccr in all groups of rats. In conclusion, carvedilol alone, but more strongly in combination with captopril, significantly reduced blood pressure, PP, LVH, renal blood vessel changes and chronic renal failure progression.

Elevated levels of circulating prorenin, the precursor of renin, have been reported to precede the appearance of microvascular complications in diabetes mellitus. Although several studies using animal models have attempted to address the link between elevated prorenin and the tissue remodeling and damage associated with both hypertension and diabetes mellitus, the results have been contradictory, and the mechanism whereby prorenin might contribute to these pathologies remains a subject of debate. To directly test the role of prorenin in these pathologies, we generated transgenic mice with selective increases (13- to 66-fold) in circulating native or active site-mutated prorenin. Systolic blood pressure was either unchanged or increased (+25 mm Hg) in native prorenin-expressing mice, whereas the mice expressing active site-mutated prorenin showed no significant differences in systolic blood pressure compared with control animals. There was no increase in cardiac fibrosis or renal glomerular sclerosis in any of the transgenic animals tested, even at an advanced age (18 months). Captopril (an angiotensin-converting enzyme inhibitor) rapidly normalized blood pressure of hyperproreninemic mice, whereas infusion of the putative antagonist of the prorenin receptor (handle region peptide) had no effect. These results suggest that the primary consequence of chronic elevations in circulating prorenin is an increase in blood pressure and do not support a role for prorenin as the primary causative agent in cardiac fibrosis or renal glomerular injury. The lack of effect seen with active site-mutated prorenin and the efficacy of angiotensin-converting enzyme inhibition are also consistent with prorenin acting through the generation of angiotensin II to raise blood pressure.

Introduction: The aim of this study was to document the impact of renin-angiotensin system (RAS) polymorphisms on renal haemodynamics and renal hormones in type 2 diabetes mellitus., Materials and Methods: Fifty-nine adult patients were studied. Renal haemodynamics were evaluated using 99mTc-MAG3 clearance (MAG3( Cle)) using Bubeck's method and captopril renogram. RAS hormones and angiotensin-converting enzyme (ACE) levels were measured before and after captopril.ACE, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms were analysed., Results: Post-captopril MAG3(Cle) values were significantly lower in patients with microalbuminuria compared to nonproteinuric patients. Statistically significant negative correlation was found between clearance percentage change values and HbA(1c) levels (r: -0.42, p=0.009). MAG3(Cle) was relatively lower following captopril administration in DD patients, while a relative increment was observed in I allele carriers (p=0.02).TheAC-CC group had significantly higher mean post-captopril clearance value compared to the AA genotype (480.9+/-56.1 ml/min/1.73 m(2) vs. 428.4+/-74.8 ml/min/1.73 m(2), p=0.022)., Conclusions: Our data indicate that the heterogeneity of patients' response to ACE inhibition is, at least partly, genetically determined, and the genetic polymorphisms in RAS might predict the acute responsiveness to ACE inhibitors.

Introduction: Growth arrest specific-6 (GAS-6), a vitamin K-dependent protein, is a potential mediator in progressive and chronic renal disease, specifically as a mediator of abnormal mesangial cell proliferation. Nitric oxide and angiotensin II affect mesangial cell proliferation. However, an association between nitric oxide synthase or angiotensin II on GAS-6 expression in the kidney has not previously been examined. Thus, our aim was to examine the effects of antihypertensive angiotensin-converting enzyme inhibitors and chronic nitric oxide synthase inhibition on the kidney expression of GAS-6 and its receptors AXL, MER and RSE., Methods: Four groups of adult male C57BL/6J mice were studied: group 1, untreated controls (tap water for six weeks); group 2, treated orally with a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 0.325 mg/ml for six weeks); group 3, treated orally with captopril (0.6875 mg/ml for six weeks); group 4, co-treated orally with L-NAME and captopril (same doses for six weeks). At the end of the study, kidneys were placed in fixative and processed to paraffin for immunohistochemical staining., Results: GAS-6 and its receptors were not present in control and L-NAME-treated mice. Positive GAS-6 staining was detectable only in those mice receiving some form of chronic dosing with captopril, whether they were treated with captopril only or with captopril and L-NAME. Immunohistochemical detection across cases for MER and RSE was rare, whereas AXL-positive staining in the kidney mirrored GAS-6 staining/expression. The staining of GAS6 and AXL was predominantly localised to the renal tubular cells., Conclusions: These findings suggest that GAS-6 may not be a final common pathway for nitric oxide synthase inhibition-induced renal disease. Renal tubular GAS-6 expression following captopril treatment was unexpected and could be beneficial in preventing tubular atrophy following the onset of persistent systemic hypertension.

This study has been initiated to determine whether captopril, an angiotensin-converting enzyme (ACE) inhibitor containing sulfhydryl (-SH) group can protect against cisplatin-induced nephrotoxicity in rats. A single dose of cisplatin (7.5 mg/kg bwt) injected i.p. caused a significant increase in blood urea nitrogen (BUN) and creatinine levels amounting to 402% and 573%, respectively with a marked elevation in lipid peroxides measured as malondialdehyde (MDA) content (54%), accompanied by a significant decrease in reduced glutathione (GSH) content (27%) of kidney tissue as compared to control group. In addition, there were marked increases in kidney tissue content of nitric oxide (NO) (43%) and plasma endothelin-1(ET-1) (37%). On the other hand, administration of captopril (60 mg/kg bwt, i.p.) 1 h before cisplatin protected the kidney as indicated by restoration of BUN, creatinine, MDA, GSH, NO and ET-1. These results indicate that captopril, an ACEI, has a protective effect against cisplatin-induced damage to kidney. This reflects the beneficial role of captopril in treatment of renovascular hypertention and congestive heart failure; an effect that may be related to its free radicals scavenging and antioxidant effects which are sulfhydryl dependent.

Objective: In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype., Design and Methods: Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril., Results: Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril., Conclusion: The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.

Purpose of this work was to study renal function in white rats following a single dose of exogenous tiroxin (T4) on a background of non-selective NO-synthase blocker or inhibition of angiotensin-1 converting enzyme. The experiment was performed with males of outbred white rats (body mass = 140-180 g). Three days prior to T4 injection, the animals drank water solution of captopril (20 mg/l) or were injected intra-gastrically with water solution of non-selective NO-synthase blocker N(omega)-NLA (1 mg/100 g of body mass) over 3 days preceding T4 injection. A single dose of sodium chloride T4 on 1% starch gel (50 microg/100 g of body mass) was injected intragastrically; 5% water loading was given one hour later. Urine and plasma samples were analyzed for osmolality; creatinine, nitrites, nitrates and proteins were measured in urine samples. Tirozine was found to moderately decrease creatinine clearance and increase excretion of proteins, osmotically active substances (OAS), nitrites and nitrates with urine, and raise concentrations of stable nitrogen oxides, primarily nitrates in blood plasma. Pre-block of ACE by captopril intensified diuresis and inhibited renal excretion of OAS, nitrites and nitrates in response to T4 injection. However, captopril failed to prevent the decrease in creatinine clearance and the level of proteinuria. Pre-block of NO synthesis resulted in marked decreases in creatinine clearance, excretion of OAS and nitrites, and moderation of diuresis comparing with intact rats and rats treated with T4 only.

Using type 1a angiotensin receptor (AT1a) receptor-deficient (Agtr1a-/-) mice and in vivo autoradiography, we tested the hypothesis that intracellular uptake of ANG II in the kidney and adrenal glands is primarily mediated by AT1a receptors and that the response is regulated by prevailing endogenous ANG II. After pretreatment of wild-type (Agtr1a+/+) and Agtr1a-/- mice (n = 6-9 each group) with or without captopril (25 mg.kg(-1).day(-1)) or losartan (10 mg.kg(-1).day(-1)) for 2 wk, [125I]Val5-ANG II was infused for 60 min. Intracellular uptake of [125I]Val5-ANG II was determined by quantitative in vivo autoradiography after washout of circulating [125I]Val5-ANG II. Basal intracellular ANG II levels were 65% lower in the kidney (P < 0.001), but plasma ANG II levels were threefold higher, in Agtr1a-/- than wild-type mice (P < 0.01). Although plasma [125I]Val5-ANG II levels were similar, urinary excretion of [125I]Val5-ANG II was fourfold higher in Agtr1a-/- mice (P < 0.001). By contrast, intracellular [125I]Val5-ANG II levels were approximately 80% lower in the kidney and adrenal glands of Agtr1a-/- mice (P < 0.01). Captopril decreased endogenous plasma and renal ANG II levels (P < 0.01) but increased intracellular uptake of [125I]Val5-ANG II in the kidney and adrenal glands of wild-type and Agtr1a-/- mice (P < 0.01). Losartan largely blocked renal and adrenal uptake of [125I]Val5-ANG II in wild-type and Agtr1a-/- mice. Thus 80% of intracellular ANG II uptake in the kidney and adrenal glands is mediated by AT1a receptors, whereas AT1b receptor- and other non-receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT1a receptor-mediated uptake of extracellular ANG II may play a physiological role in the kidney and adrenal glands.

Objective: We compared the renal vascular response to captopril and candesartan among nondiabetic, normotensive black and white participants to explore angiotensin-converting enzyme-independent generation of angiotensin II., Methods: Thirteen black individuals and 10 white individuals in low-salt balance were given captopril and candesartan on sequential study days, and the renal plasma flow responses to these agents were measured., Results: Consistent with our prior observations, white individuals demonstrated a strong, significant correlation between responses to these drugs (r = 0.78, P = 0.008) and a significantly greater increase in the renal plasma flow in response to candesartan compared with captopril (104.2 +/- 26.8 versus 52.4 +/- 24.3 ml/min per 1.73 m; P = 0.03). In black participants, however, no correlation between responses to captopril and to candesartan was observed (r = 0.22, P = 0.47) and there was no difference in the renal plasma flow response between the two drugs (90.4 +/- 13.0 versus 80.4 +/- 15.3 ml/min per 1.73 m; P = 0.59). The difference in the response to the two drugs was significantly higher among white participants compared with black participants (P = 0.03)., Conclusion: We confirmed the contribution of an angiotensin-converting enzyme-independent pathway for angiotensin II generation in the kidneys of nondiabetic, normotensive white, but not black, individuals.

Angiotensin-converting enzyme inhibitors (ACEis) are known to have antifibrotic effects on the heart and kidney in both animal models and humans. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of proliferation of hematopoietic stem cells and a natural substrate of ACEi that was reported to prevent cardiac and renal fibrosis in vivo. However, it is not clear whether N-acetyl-seryl-aspartyl-lysyl-proline participates in the antifibrotic effects of ACEi. To clarify this issue, we used a model of aldosterone-salt-induced hypertension in rats treated with the ACEi captopril either alone or combined with an anti-N-acetyl-seryl-aspartyl-lysyl-proline monoclonal antibody. These hypertensive rats had the following: (1) left ventricular and renal hypertrophy, as well as increased collagen deposition in the left ventricular and the kidney; (2) glomerular matrix expansion; and (3) increased ED1-positive cells and enhanced phosphorylated-p42/44 mitogen-activated protein kinase in the left ventricle and kidney. The ACEi alone significantly lowered systolic blood pressure (P=0.008) with no effect on organ hypertrophy; it significantly lowered left ventricular collagen content, and this effect was blocked by the monoclonal antibody as confirmed by the histological data. As expected, the ACEi significantly decreased renal collagen deposition and glomerular matrix expansion, and these effects were attenuated by the monoclonal antibody. Likewise, the ACEi significantly decreased ED1-positive cells and inhibited p42/44 mitogen-activated protein kinase phosphorylation in the left ventricle and kidney, and these effects were blocked by the monoclonal antibody. We concluded that in aldosterone-salt-induced hypertension, the antifibrotic effect of ACEi on the heart and kidney, is partially mediated by N-acetyl-seryl-aspartyl-lysyl-proline, resulting in decreased inflammatory cell infiltration and p42/44 mitogen-activated protein kinase activation.

Onset of diabetes increases plasma renin activity (PRA) and glomerular filtration rate (GFR), but blood pressure (BP) is normal. In this study, a 70% surgical reduction in kidney mass (RK) was used to decrease baseline GFR and to prevent hyperfiltration during diabetes, and angiotensin converting enzyme inhibitors (ACEI) were used to inhibit angiotensin II (AngII) production, to test the hypothesis that a balance between GFR and AngII is required for normal BP early in diabetes. Diabetes was induced with streptozotocin (STZ) (35 mg/kg intravenously); and after 7 days of hyperglycemia (range: 408 to 486 mg/dL), insulin was intravenously infused continuously for a 4-day normoglycemic recovery period. In normal kidney (NK) rats, diabetes increased PRA (2.4 +/- 0.6 to 4.6 +/- 0.5 ngAI/mL/h) and GFR (2.9 +/- 0.1 to 3.5 +/- 0.2 mL/min), and there was no change in mean arterial pressure (MAP) (89 +/- 1 v 91 +/- 1 mm Hg, measured 18 h/day). There was no change in either GFR or AngII during diabetes in RK+ACEI rats, and their MAP also did not change. Thus, the maintenance of normal MAP was accompanied by a balance between GFR and AngII in both of those groups. In NK+ACEI rats, however, GFR increased significantly with no change in AngII, and MAP decreased significantly during diabetes by approximately 8 mm Hg. In RK rats, PRA increased (0.5 +/- 0.1 to 2.6 +/- 0.5) but GFR did not increase, and MAP increased significantly by approximately 16 mm Hg. All rats were in sodium balance by day 4 of diabetes. These data support the hypothesis that normotension early in diabetes requires a balance between the increased AngII and GFR, and that BP will increase if AngII increases but GFR does not.

Renin is the rate-limiting enzyme in the renin-angiotensin system and thus dictates the level of the pressor hormone angiotensin-II. The classical site of renin expression and secretion is the renal juxtaglomerular cell, where its expression is tightly regulated by physiological cues. An evolutionarily conserved transcriptional enhancer located 11 kb upstream of the human RENIN gene has been reported to markedly enhance transcription in renin expressing cells in vitro. However, its importance in vivo remains unclear. We tested whether this enhancer is required for appropriate tissue- and cell-specific expression, or for physiological regulation of the human RENIN gene. To accomplish this, we used a retrofitting technique employing homologous recombination in bacteria to delete the enhancer from a 160-kb P1-artificial chromosome containing human RENIN, two upstream genes and one downstream gene, and then generated two lines of transgenic mice. We previously showed that human renin expression in transgenic mice containing the wild type construct is tightly regulated as is expression of the linked genes. Deletion of the enhancer had no effect on tissue-specific expression of human RENIN, but using the downstream gene as an internal control, found that human RENIN mRNA levels were 3-10-fold decreased compared with constructs containing the enhancer. Despite this decrease in expression, renin protein remained localized to renal juxtaglomerular cells and was appropriately regulated by cues that either increase or decrease expression of renin. Our results suggest that sequences other than the enhancer may be necessary for tissue-specific, cell-specific, and regulated expression of human RENIN.

Although angiotensin-converting enzyme (ACE) inhibitors are well-established drugs in the treatment of hypertension, they are not supposed to be sufficient in the inhibition of aldosterone formation. The present study analyzes the effect of aldosterone receptor antagonist, spironolactone and ACE inhibitor, captopril on nitric oxide (NO) and S-nitrosothiol formation in the kidney of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Male Wistar rats were divided into six groups: (1) controls, (2) L-NAME (40 mg/kg/day), (3) spironolactone (200 mg/kg/day), (4) captopril (100 mg/kg/day), (5) L-NAME+spironolactone, and (6) L-NAME+captopril. After 4 weeks, NO synthase (NOS) activity, protein expression of endothelial NOS, inducible NOS and concentration of thiol and S-nitrosothiol groups were determined in the kidney. Besides the increase in systolic blood pressure (by 32%) and the decrease in NOS activity (by 37%), L-NAME treatment lowered the concentration of thiols (by 32%) and S-nitrosothiols (by 36%) in the renal tissue. Simultaneous treatment with spironolactone preserved NOS activity and S-nitrosothiols on the control level, whereas captopril did not affect these parameters modified by L-NAME treatment. Moreover, spironolactone increased expression of endothelial NOS protein without affecting inducible NOS protein expression. In conclusion, both captopril and spironolactone prevented L-NAME-induced hypertension and the decline of the antioxidant potential of the kidney tissue. However, only spironolactone improved NOS activity which led to the S-nitrosothiols formation. Both NO itself and S-nitrosothiols may contribute to the preventive effect of spironolactone against development of L-NAME-induced hypertension.

Myocardial infarction (MI) activates the renin-angiotensin system in the heart and increases local production of aldosterone. This hormone may increase reactive fibrosis in the myocardium favoring heart failure development. To elucidate the potential contribution of aldosterone to cardiac remodeling following MI, we evaluated the expression of mineralocorticoid receptors (MCR) in the left ventricle (LV) and kidney of rats after MI and captopril treatment. MI was induced by ligation of the coronary artery in Wistar rats, which were separated into (1) sham-operated group, (2) MI group, (3) MI-captopril treated group (cap, 50 mg kg(-1) day(-1)). One month later angiotensin converting enzyme (ACE) activity was assayed in the plasma, LV and kidney. Cardiac and renal angiotensin II (Ang II) levels were determined by ELISA and MCR mRNA expression and protein were measured by Taqman RT-PCR and Western blot, respectively. Cardiac MCR mRNA and protein levels increased nearly by 80% after MI and Cap treatment normalized cardiac MCR protein and mRNA expression. Kidney MCR expression was not affected. ACE activity increased 34% in the plasma and 83% in the LV after MI. This increase was prevented by Cap. Ang II concentration increased 225% in the LV and 193% in kidney, which was partially attenuated by Cap. Our data demonstrate upregulation of MCR in the heart following MI what may facilitate the effects of aldosterone in the ventricular remodeling process. ACE inhibitors may reduce reactive fibrosis not only by decreasing Ang II production but also by attenuating the aldosterone-signaling pathway by decreasing the expression of MCR receptors.

The administration of thyroxin (10 microg/100 g body weight, 7 days) in rats leads to an increase in the renal excretion of proteins and nitrates. Under the conditions of hypo- and normosodium diet, thyroxin decreased the rate of glomerular filtration. Hypersodium diet and captopril increased the rate of glomerular filtration in rats with experimental hyperthyreosis. The maximum level of renal excretion in hyperthyreoidal rats was observed on the background of sodium-rich diet.

High glucose concentrations are involved in the development of diabetic-associated vascular complications. We have previously reported that acute high glucose challenge, corresponding to post-prandial glycemia levels observed in patients with type 2 diabetes, blunts ACh-induced endothelium-dependent relaxation of the renal circulation of non-diabetic rabbits. Isolated perfused kidneys from non-diabetic rabbits were acutely exposed (3 h) to normal (5.5 mM--control group) or high (15 mM) D-glucose concentrations in the presence or absence of a continuous infusion of metformin (20 or 100 microM). Renal vascular reactivity was evaluated with endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) vasodilating agents. ACh-induced maximal renal vasodilation was reduced by high glucose infusion (15 mM) in comparison to the control group (25+/-3% and 41+/-3% respectively; P<0.01), being restored to 41+/-4% and 43+/-2% by a simultaneous 3-h infusion of 20 or 100 microM of metformin respectively (P>0.05). Perfusion of the kidneys with the angiotensin II-converting enzyme inhibitor captopril (10 microM) also significantly prevented the deleterious effects of high glucose challenge in the renal circulation. The use of a continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) did not affect the protective effect of metformin in the renal circulation (39+/-4%; P>0.05), while tetraethylammonium (TEA, 10 mM) partially blunted this effect (33+/-4, P<0.01). Renal vasodilation induced by SNP was not modified by simultaneous infusion of high glucose and/or metformin. It is concluded that the impairment of ACh-induced endothelium-dependent renal vasodilation observed after acute exposure to high glucose concentrations is abolished by metformin administration. These alterations of renal vascular reactivity can be accounted for, at least in part, by the activation of the renal renin-angiotensin system during hyperglycemia. The protective effects of metformin present some EDHF-dependent component and are not related to metabolic pathways dependent on nitric oxide.

Objective: To investigate the changes and the effects of captopril on the renal blood flow and microvascular perfusion in dogs with acute cardiac insufficiency., Methods: Acute cardial insufficiency was induced by combining occlusion of the left anterior descending artery with right ventricular pacing in 12 mongrel dogs. The ascending aorta and left kidney were dissected and ultrasonic flow probes were placed on ascending aorta and renal artery to monitor cardiac output (CO) and renal blood flow (RBF). Contrast-enhanced ultrasound of the kidney was performed as CO was reduced to 25% (LCO25%) and 50% (LCO50%) from the basic measurement and microvascular flow velocity (beta), microvascular volume (A) and microvascular blood flow (renal cortex) were observed. After CO reduced to 50%, captopril 1 mg/kg and 2 mg/kg were injected successively and contrast-enhanced ultrasound of the kidney were performed again before and after injection., Results: At baseline, CO, RBF, CXbeta (beta of renal cortex), A and A x beta were (1.46 +/- 0.16) ml/min, (107.5 +/- 35.7) ml/min, 1.39 +/- 0.14, 120.3 +/- 14.8 and 167.4 +/- 25.0, respectively. After the LCO25% was reached, RAF, CXbeta, A and A x beta decreased to (72.50 +/- 32.4) ml/min, 0.87 +/- 0.082, 117.6 +/- 13.1, and 102.6 +/- 15.5, respectively. The corresponding values after the LCO50% was reached were (44.1 +/- 17.2) ml/min, 0.61 +/- 0.039, 106.9 +/- 12.0, and 64.7 +/- 8.83, respectively. It is suggested that the volume of the renal microvasculature remained stable until the LCO50% was reached. When captopril 1 mg/kg and 2 mg/kg were injected successively at LCO50%, MAP decreased from (85.4 +/- 7.8) mm Hg to (78.7 +/- 7.3) mm Hg and to (69.1 +/- 6.3) mm Hg (P < 0.05), respectively, while CO increased from 0.73 +/- 0.084 to 0.83 +/- 0.065 and to 0.9 +/- 0.054 (P < 0.05), respectively. RBF increased from (44.1 +/- 17.2) ml/min to 60.3 +/- 17.8 and to 79.4 +/- 17.8 (P < 0.05), respectively. After captopril 1 mg/kg and 2 mg/kg were injected, the increased flow ratios with CO were 0.15 +/- 0.084 and 0.31 +/- 0.011, respectively, and with RBF were 0.29 +/- 089 and 0.522 +/- 0.040, respectively. The increased renal blood flow ratio was higher than that of CO after captopril was used. The corresponding increases were from 0.61 +/- 0.039 to 0.75 +/- 0.020 and to 0.86 +/- 0.027 for CX beta, from 106.9 +/- 11.9 to 115.4 +/- 11.1 and to 116.6 +/- 8.9 for A, from 64.7 +/- 8.83 to 87.0 +/- 8.6 and to 100.6 +/- 8.9 for A x beta, respectively., Conclusion: The renal microvasculature plays a role by keeping its volume stable in the protection against renal ischemia when acute cardiac output decreases slightly. The role of captopril to improve renal microvascular perfusion is independent of increased total cardiac output or increased systemic blood pressure.

In previous studies, we have demonstrated that the low molecular weight protein lysozyme can be used as a renal-selective drug carrier for delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril. Typically, such macromolecular drug-targeting preparations are administered intravenously. In the present study, we investigated the fate of captopril-lysozyme following subcutaneous administration, a convenient route for long-term treatment. The absorption from the subcutaneous injection site and renal uptake of lysozyme were determined by gamma scintigraphy in rats. Bioavailability, renal accumulation, and stability of the captopril-lysozyme conjugate were evaluated by high performance liquid chromatography analysis and by ACE activity measurements. Lysozyme was absorbed gradually and completely from the subcutaneous injection site within 24 h and accumulated specifically in kidneys. After subcutaneous injection of the captopril-lysozyme conjugate, higher renal captopril levels and lower captopril-lysozyme levels in urine indicated the improved renal accumulation in comparison with intravenous administration of the conjugate, as well as its stability at the injection site. After both treatments, captopril-lysozyme conjugate effectuated renal ACE inhibition, whereas plasma ACE was not inhibited. In conclusion, our results demonstrate that we can use the subcutaneous route to administer drug delivery preparations like the captopril-lysozyme conjugate.