enalapril and Nephritis

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Cell Line; Cytokines; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Enalapril; Guanylyl Cyclase C Agonists; Humans; Inflammation Mediators; Kidney Tubules, Proximal; Male; Nephritis; Phosphorylation; Pyrazoles; Pyrimidines; Rats, Zucker; Signal Transduction; Smad3 Protein

Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD.. We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin-system (RAS).. The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice.. This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Kidney; Losartan; Mice; Nephritis; Renin-Angiotensin System

The search for new therapies providing cardiorenal protection in chronic kidney disease (CKD) has led to treatments that combine conventional renin-angiotensin-aldosterone-system inhibitors with other drugs that exhibit potential in disease management.. In rats made uremic by renal ablation, we examined the effects of addition of the endothelin-A receptor antagonist atrasentan to a previously examined combination of enalapril (angiotensin converting enzyme inhibitor) and paricalcitol (vitamin D receptor activator) on cardiac and renal parameters. The effects of the individual and combined drugs were examined after a 3-month treatment.. A decrease in systolic blood pressure, serum creatinine and proteinuria, and improvement of renal histology in uremic rats were attributed to enalapril and/or paricalcitol treatment; atrasentan alone had no effect. In heart tissue, individual treatment with the drugs blunted the increase in cardiomyocyte size, and combined treatment additively decreased cardiomyocyte size to normal levels. Perivascular fibrosis was blunted in uremic control rats with atrasentan or enalapril treatment.. We found distinct cardiac and renal effects of atrasentan. Combination treatment with atrasentan, enalapril and paricalcitol provided positive effects on cardiac remodeling in uremic rats, whereas combination treatment did not offer further protective effects on blood pressure, proteinuria or renal histology.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Bone Density Conservation Agents; Drug Therapy, Combination; Enalapril; Endothelin Receptor Antagonists; Ergocalciferols; Female; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Function Tests; Myocardium; Nephrectomy; Nephritis; Pyrrolidines; Rats; Rats, Sprague-Dawley; Survival Analysis; Uremia

In this study, we explored the mechanisms by which the angiotensin converting enzyme inhibitor (ACEI), enalapril, and the Ang II receptor blocker (ARB), losartan suppress oxidative stress and NF-κB activation-induced inflammatory responses in aged rat kidney. The experimentations were carried out utilizing aged (24-month-old) Brown Norway×Fischer 344 (F1) male rats which were randomized into 3 groups and administered enalapril (40 mg/kg), losartan (30 mg/kg) or placebo for 6 months (daily p.o.). The level of reactive species (RS), peroxynitrite (ONOO(-)), GSH/GSSG and lipid peroxidation were measured. The activity of the pro-inflammatory transcription factor NF-κB, and gene expression of proteins in upstream signaling cascades were measured by electro-mobility shift assay (EMSA) and Western blotting. Enalapril and losartan differentially attenuated redox imbalance and the redox-sensitive transcription factor, the NF-κB pathway. Furthermore, stimulation of the NF-κB activation pathway by phosphorylation of p65 was attenuated by both compounds. Moreover, mediation of phosphorylation of p65 by phosphorylation of IκB kinase αβ (IKKαβ) and mitogen- and stress-activated protein kinase-1 (MSK-1), were also inhibited by enalapril and losartan. Finally, both compounds also lowered expression of NF-κB-dependent inflammatory genes, such as cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS). Only losartan lowered levels of 5-lipoxygenase (5-LOX). These findings indicate that enalapril and losartan differentially suppress inflammatory responses via inhibition of oxidative stress-induced NF-κB activation in aged rat kidney.

Topics: Aging; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Gene Expression; Kidney; Losartan; Male; MAP Kinase Signaling System; Nephritis; NF-kappa B; Oxidative Stress; Phosphorylation; Random Allocation; Rats; Rats, Inbred BN; Rats, Inbred F344; Transcription Factor RelA

TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Blood Urea Nitrogen; Cells, Cultured; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Macrophages; Mesangial Cells; Nephrectomy; Nephritis; NF-kappa B; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Transfection; Tumor Necrosis Factor-alpha

Previous studies have demonstrated that enalapril and verapamil seem to attenuate the cyclosporine nephrotoxicity. However, the mechanisms have not been completely understood, especially on molecular events. The aim of this study was to examine the effect of individual or combined treatment on osteopontin, TGF-beta, endothelin-1 and procollagen alpha 1(I) mRNA expressions. Enalapril (50 mg/L in drinking water) and verapamil (0.5 mg/kg/day, subcutaneously), alone or in combination, were administered to rats with chronic cyclosporine nephrotoxicity (cyclosporine, 25 mg/kg/day, subcutaneously) (n = 5 each). Five rats treated with olive oil vehicle were used as control. After 4 weeks, biochemical parameters were measured, and renal cortical mRNA levels were evaluated by Northern blot analysis. Cyclosporine reduced renal creatinine clearance significantly and induced renal cortical osteopontin, TGF-beta, endothelin-1 and procollagen alpha 1(I) gene expressions around 13.5 +/- 1.3, 2.4 +/- 0.2, 1.5 +/- 0.1, 1.9 +/- 0.1 folds, respectively. Individual treatment with enalapril or verapamil significantly suppressed the osteopontin and TGF-beta mRNA expression, but not endothelin-1 and procollagen alpha 1(I). Combined treatment also inhibited the osteopontin and TGF-beta mRNA expression but there was no difference between combined and individual treatment. In conclusion, enalapril or verapamil significantly blunted the cyclosporine-induced osteopontin and TGF-beta gene expressions. However, combined treatment did not show any additive effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Cyclosporine; Drug Therapy, Combination; Enalapril; Endothelin-1; Gene Expression Regulation; Immunosuppressive Agents; Kidney Cortex; Male; Nephritis; Osteopontin; Procollagen; Rats; Rats, Wistar; RNA, Messenger; Sialoglycoproteins; Transforming Growth Factor beta; Verapamil

Radiation of the kidney often leads to renal failure. The contribution of arterial hypertension to the development of this complication is unclear. The aim of this study was to determine the renal effects of antihypertensive therapy in 1- and 2-kidney rat models of radiation nephritis. Five groups of Long Evans rats had X-irradiation of the left kidney. In groups 1 and 2, the right kidney was left undisturbed (2-kidney model). The rats in group 3, 4 and 5 underwent right nephrectomy 21 days before radiation (1-kidney model). Groups 1 and 3 received no drug treatment and served as controls for each model. Groups 2 and 4 had enalapril 50 mg/l in drinking water and group 5 hydrochlorothiazide (HCT) 200 mg/l, also in drinking water. Blood pressure increased significantly in both control groups and remained normal throughout the study in all treated groups. At the end of the study, mean urinary protein excretion was lower in the two enalapril-treated groups but not in HCT-treated animals. Groups 1 and 2 (2-kidney models) showed similar increments in plasma creatinine (PCreat), and, in both groups, the creatinine clearance (CCreat) dropped to the same extent. Among nephrectomized animals (1-kidney model), PCreat was lower and CCreat higher in the enalapril-treated group. Consistent with these findings, glomerular sclerosis was less severe in both enalapril-treated groups. We conclude that, in radiation nephritis, lowering blood pressure with enalapril exerts a beneficial effect on renal function and structure, whereas a similar reduction in blood pressure induced by HCT does not.

Topics: Animals; Blood Pressure; Enalapril; Hydrochlorothiazide; Hypertension, Renal; Nephrectomy; Nephritis; Radiation Injuries, Experimental; Rats; Time Factors

A previous study showed that radiation nephritis could be treated with captopril, an angiotensin-converting-enzyme inhibitor. These studies were designed to determine whether other angiotensin-converting-enzyme inhibitors would be effective, whether captopril would inhibit the development of the histopathologic lesions typical of radiation nephritis, and whether captopril could be used to treat the nephropathy observed in bone marrow transplant recipients conditioned with total body irradiation.. In radiation nephritis studies, rats were given 17-27 Gy bilateral renal irradiation in 5 fractions. Six months after irradiation animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l) or enalapril (50 mg/l) in the drinking water. A subset of animals was sacrificed for histopathology after 3 months; the remaining animals continued on drugs for 7 months. In the bone marrow transplant nephropathy study, rats received 14-17 Gy total body irradiation in 6 fractions over 3 days followed by syngeneic bone marrow transplant. Six months after irradiation, animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l). Animals remained on drugs for 6 months. In all studies animals were followed with periodic renal function tests.. In the radiation nephritis study, survival and renal function were significantly enhanced by both captopril and enalapril, but there were no significant differences between the drugs. The histopathologic severity of the lesions of radiation nephritis correlated with the degree of renal dysfunction; and in irradiated animals with equal initial azotemia, captopril-treated rats developed less severe renal lesions. Finally, captopril also prolonged survival and preserved renal function in this rat bone marrow transplant nephropathy model.. Angiotensin-converting-enzyme inhibitors are an effective treatment for both radiation nephritis and bone marrow transplant nephropathy.

Topics: Animals; Blood Urea Nitrogen; Bone Marrow Transplantation; Captopril; Drug Evaluation, Preclinical; Enalapril; Female; Kidney; Male; Nephritis; Radiation Injuries, Experimental; Rats; Whole-Body Irradiation

Albuminuria (UalbV) increases in proportion to dietary protein in rats with passive Heymann nephritis. To determine whether a similar relationship existed in normal animals, 14 normal rats were switched from an 8.5% protein diet (LP) to a 40% protein diet (HP). Initially UalbV and glomerular filtration rate (GFR) increased in parallel, but GFR ceased to increase after 48 h while UalbV continued to increase, causing a significant increase in fractional renal clearance of albumin (FCalb). In contrast, HP for 4 days caused only a transient increase in GFR in nephrotic rats but effected a threefold sustained increase in UalbV. Pretreatment of nephrotic rats with enalapril blunted but did not entirely prevent the increase in UalbV after switching to HP and did not affect the increase or subsequent decline in GFR. Treatment with enalapril for 10 days reduced UalbV and FCalb in nephrotic rats fed either LP or HP. The similar pattern of changes in urinary albumin excretion in normal and nephrotic rats after dietary protein augmentation suggests that dietary protein may modify UalbV by the same process in both normal and nephrotic animals. The increases in UalbV and GFR resulting from dietary protein augmentation represent parallel but independent processes, since only the proteinuric response is modified by converting enzyme inhibition. Dietary protein restriction and converting enzyme inhibition exert an additive effect to reduce UalbV.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Dietary Proteins; Enalapril; Glomerular Filtration Rate; Kidney; Male; Nephritis; Proteinuria; Rats; Rats, Inbred Strains; Time Factors

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.

Topics: Angiotensin II; Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Kidney Tubules, Proximal; Nephritis; Nephrons; Rats; Rats, Inbred Strains; Reference Values; Renin-Angiotensin System

To determine if changes in dietary protein intake alter renal excretion of small molecular weight proteins in passive Heymann nephritis, 21 rats with passive Heymann nephritis were fed 8.5% protein for 12 days after injection with antiserum. Dietary protein intake was then increased to 40% in 10 rats (LP-HP) while 11 rats remained on 8.5% protein (LP-LP). Lysozymuria (UlysV) increased from 66.5 +/- 31.0 mcg/day to 457.5 +/- 98.0 mcg/day (P less than 0.001) after five days in LP-HP, but was unchanged in LP-LP. Albuminuria (UalbV) increased only in LP-HP, from 168 +/- 23 mg/day to 447 +/- 45 mg/day (P less than 0.001). Urinary lysozyme excretion correlated with UalbV (r = 0.737, P less than 0.001), and changes in UlysV correlated with changes in UalbV (r = 0.657, P less than 0.01). To determine whether the increase in UlysV was the direct effect of the change in diet, enalapril 40 mg/kg/day was administered to prevent the increase in UalbV that occurs when these rats are fed a high protein diet. Twelve rats were fed 8.5% (LP) and 10 were fed 40% protein (HP) from the time of injection with antiserum. Six LP (LPE) and five HP (HPE) received enalapril. UlysV was 873 +/- 391 mcg/day in HP and nearly undetectable in the other three groups. UalbV was significantly greater in HP (368 +/- 60 mg/day) compared to the other three groups (114 +/- 16 in LP, 136 +/- 44 in HPE, 95 +/- 21 in LPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Animals; Dietary Proteins; Enalapril; Glomerular Filtration Rate; Male; Muramidase; Nephritis; Rats; Rats, Inbred Strains

1. Nephrotoxic serum nephritis was induced immunologically in uninephrectomized Sprague-Dawley rats (n = 24). One-half were assigned randomly to treatment with enalapril (5 mg/kg per 24 h). 2. Untreated rats (n = 12) developed a progressive fall in creatinine clearance, a progressive rise in systolic blood pressure and marked proteinuria over a 6 week period. The mortality rate was 42% at 5 weeks and 66% at 6 weeks. 3. Enalapril-treated rats (n = 12) had no significant reduction in systolic blood pressure, and a similar reduction in creatinine clearance to that in untreated rats. Mortality was 50% at 5 weeks, and 92% at 6 weeks. 4. Proteinuria but not the blood pressure rise was significantly reduced by enalapril treatment. 5. Converting enzyme inhibitors may have a specific role in the treatment of nephritic diseases.

Topics: Animals; Blood Pressure; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Kidney Failure, Chronic; Nephritis; Proteinuria; Rats; Rats, Inbred Strains