enalapril and Nephritis--Interstitial

Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies.. We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug.. Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases.. Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension, Renal; Inulin; Kidney Failure, Chronic; Kidney Function Tests; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial; p-Aminohippuric Acid; Ramipril; Renal Circulation

Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.. Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg(-1)·d(-1), ip), or BSA plus enalapril (0.5 g·kg(-1)·d(-1), po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.. BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68(+) cells (macrophages) and CD3(+) cells (T lymphocytes), particularly of CD20(+) cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.. Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation.

Topics: Animals; B-Lymphocytes; Carrier Proteins; Caspase 1; Enalapril; Epithelial Cells; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Kidney Tubules, Proximal; Macrophages; Male; Nephrectomy; Nephritis, Interstitial; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Serum Albumin, Bovine; T-Lymphocytes

To investigate the effect of enalapril on renal interstitial fibrosis in rats with unilateral ureteral obstruction(UUO).. UUO model was induced by ligating the left ureter in rats. Male Sprague-Dawley(SD) rats were randomly divided into a sham-operated group(n=16), a UUO model group(n=24), and an enalapril treated group(n=24). The rats were treated with 10 mg/kg.d by gastric gavage in the enalapril treated group from 24 h before the operation, and the rats were treated with the identical dose of normal saline in the other 2 groups. The rats were sacrificed at 3,7,14, and 21 days after UUO. Pathological changes of the renal tissue were observed by HE and Masson staining, the mRNA expression of collagen I (Col I) was detected by real-time PCR, and the protein expression of connective tissue growth factor (CTGF) was detected by Western blot.. The renal interstitial damage index, relative collagen area and the expression of Col I mRNA and CTGF in the renal tissues in the model group increased with the prolongation of obstruction. Enalapril significantly reduced the renal interstitial damage index and relative collagen area, and inhibted the expression of Col I mRNA and CTGF. There was significant difference on day 3,7,and 14 (P<0.05), but not on day 21 (P>0.05).. Enalapril significantly attenuates renal interstitial fibrosis by supressing the expression of Col I mRNA and CTGF.

Topics: Animals; Collagen Type I; Connective Tissue Growth Factor; Enalapril; Male; Nephritis, Interstitial; Nephrosclerosis; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Ureteral Obstruction

Angiotensin II plays a central role in the progression of chronic renal failure (CRF), and administration of angiotensin-converting enzyme inhibitor (ACEI) in rats delays the progression of CRF. However, ACEI has little effect on CRF progression in rats with established CRF. We therefore examined whether combination therapy with ACEI and oral adsorbent for uremic toxins in the gastrointestinal tract has the desired effect.. Rats subjected to subtotal nephrectomy were given enalapril at 20 mg/kg (n = 10, group E), AST-120 at 5 g (n = 10, group A), enalapril and AST-120 together at the same doses (n = 10, group EA), or no treatment (n = 10, group C) 8 weeks after the operation. The substances were administered in 100 g rat chow. All animals were pair-fed, and all were killed after 8 weeks of pair-feeding.. Body weight did not differ between groups during the study. Blood pressure at week 8 was significantly lower in groups E and EA than in groups C and A (p < 0.05). Urinary protein excretion level and renal plasma flow rate at week 8 were significantly less in groups E and EA than in group C (p < 0.05, p < 0.01). The glomerular filtration rate at week 8 was significantly higher in group EA than in group C (p < 0.05). The glomerular sclerosis index and interstitial fibrosis area at week 8 were significantly less in group EA than in group C (p < 0.01).. ACEI and AST-120 in combination can delay progression of established CRF in rats by inhibiting the appearance of glomerular sclerosis and interstitial fibrosis.

Topics: Adsorption; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Urea Nitrogen; Carbon; Creatinine; Drug Therapy, Combination; Enalapril; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephritis, Interstitial; Oxides; Rats; Rats, Sprague-Dawley; Sorption Detoxification; Uremia

Hyperoxaluria is a recognized cause of tubulointerstitial lesions and it may contribute to chronic renal failure. In previous studies we demonstrated that enalapril was effective against the progression of tubulointerstitial lesions in a 4-week hyperoxaluria rat model. We evaluated whether the action of enalapril on the tubulointerstitial lesions produced by hyperoxaluria persisted for a long period.. Two-month-old male Sprague-Dawley rats were divided into 4 groups of 12 each, including 1--control animals given tap water, 2--animals with hyperoxaluria, 3--animals with hyperoxaluria plus enalapril, 4--animals with enalapril. Hyperoxaluria in groups 2 and 3 rats was induced by administering 1% ethylene glycol, a precursor for oxalates, in the tap water continuously throughout the whole study. Meanwhile, groups 3 and 4 received 20 mg./l. enalapril in the drinking water. At the end of the study renal tubulointerstitial lesions were evaluated by immunostaining using monoclonal antibodies against macrophage infiltrates (ED1), tubulointerstitial alpha-smooth muscle actin and transforming growth factor-beta1. The lesions were quantified by semiquantitative scores. Creatinine clearance and urinary albumin excretion were also determined.. There was no difference in urine oxalate excretion in groups 2 and 3. Group 3 rats treated with enalapril showed fewer tubulointerstitial lesions than nontreated group 2 rats, as indicated by the mean scores plus or minus standard error of mean for inflammatory infiltrate (2.16 +/- 0.2 versus 0.83 +/- 0.16), tubular atrophy (2 +/- 0.27 versus 0.66 +/- 0.14), interstitial fibrosis (2.5 +/- 0.15 versus 0.5 +/- 0.1), glomerular ED1 (1.75 +/- 0.25 versus 0.16 +/- 0.11), interstitial ED1 (2.33 +/- 0.18 versus 0.58 +/- 0.10) tubular transforming growth factor-beta1 (2.09 +/- 0.08 versus 0.91 +/- 0.14), interstitial transforming growth factor-beta 1 (2.33 +/- 0.22 versus 0.66 +/- 0.12), tubulointerstitial alpha-smooth muscle actin (2.91 +/- 0.22 versus 0.83 +/- 0.16), lower urinary albumin excretion (35.5 +/- 2.7 mg. daily versus 10.9 +/- 1) and higher creatinine clearance (2.29 +/- 0.04 ml. per minute versus 2.54 +/- 0.03, all p <0.05).. Based on our results we believe that enalapril would provide a beneficial effect against chronic tubulointerstitial lesions caused by oxalates.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Disease Models, Animal; Enalapril; Hyperoxaluria; Immunohistochemistry; Kidney Function Tests; Male; Nephritis, Interstitial; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Treatment Outcome; Urinalysis

Hyperoxaluria is a recognized cause of tubulointerstitial lesions, and this could contribute to development of hypertension and chronic renal failure. Enalapril has been effective against the progression of tubulointerstitial lesions in various animal models. The aim of the present study was to evaluate the usefulness of enalapril on the tubulointerstitial damage produced by oxalates. Two-month-old male Sprague-Dawley rats were separated into 4 groups, control with tap water (G1), hyperoxaluric (G2), hyperoxaluric+enalapril (G3), enalapril (G4), for 4 weeks. G2 and G3 rats were given 1% ethyleneglycol (ETG, precursor for oxalates), and G3 and G4 rats were given enalapril 20 mg/L in drinking water. At the end of the study, we evaluated renal tubulointerstitial lesions by a semiquantitative score. Urine albumin excretion, serum and urine nitric oxide production, tubulointerstitial immunostaining by alpha-smooth muscle actin, transforming growth factor-beta1, and collagen type III were measured. Rats belonging to the hyperoxaluric group treated with enalapril (G3) showed fewer tubulointerstitial lesions (1.3+/-0.2 versus 3+/-0.2; P<0.01), lower urine albumin excretion (8+/-2 mg/d versus 25+/-2 mg/d; P<0.01), less percentage of alpha-smooth muscle actin in renal interstitium (2+/-0.4% versus 13.5+/-2.4%; P<0.01), less percentage of transforming growth factor-beta1 in tubulointerstitial area (3.3+/-1% versus 13.3+/-2. 1%; P<0.01), less percentage of collagen type III interstitial deposition (0.7+/-0.5% versus 7+/-2.6%; P<0.01), and increased NO production in serum as well as urine (both P<0.01), when compared with the hyperoxaluric group not treated with enalapril (G2). Considering these data, we believe that enalapril, by several mechanisms of action, could provide an important benefit in the prevention of inflammatory response, transforming growth factor-beta1 tubulointerstitial production, collagen type III interstitial deposition, and finally, the progressive tubulointerstitial fibrosis caused by oxalates.

Topics: Animals; Atrophy; Blood Pressure; Enalapril; Hyperoxaluria; Kidney Tubules; Male; Nephritis, Interstitial; Oxalates; Rats; Rats, Sprague-Dawley; Time Factors

The nephrotic mouse (ICGN strain) is a useful model for progressive nephrotic syndrome (NS). In the present study, we demonstrated the preventive effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on the progression of renal dysfunction and tubulo-interstitial fibrosis in the NS mice. Administration of enalapril (5 mg/dL in drinking water) to the 4-week-old NS mice for a 4-week-period did not improve their nephrotic symptoms such as albuminuria and hypoalbuminemia, but significantly suppressed the increases in blood urea nitrogen and serum creatinine levels. Renal histopathology demonstrated that the administration of the ACE inhibitor significantly attenuated the progression of the tubular and interstitial lesions (tubular dilatation, luminal cast accumulation and interstitial expansion) rather than the glomerular sclerotic changes. The suppression of the increase in blood urea nitrogen level by enalapril depended on the attenuated tubular injury rather than on the unchanged glomerular matrix deposition. Immunohistochemical examination revealed that the administration of the ACE inhibitor suppressed the formation of myofibroblasts, identified by the alpha-smooth muscle actin-positive cells, in the interstitial spaces. Consequently, interstitial matrix deposition was significantly reduced in the NS mice treated with enalapril. From the results obtained with the spontaneous nephrotic model, we emphasize a possibility that ACE inhibitor may be effective for attenuating progression of renal dysfunction and fibrosis in human NS, even if the ACE inhibitor fails to improve nephrotic symptoms such as albuminuria and hypoalbuminemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Progression; Enalapril; Extracellular Matrix Proteins; Female; Fibroblasts; Kidney; Male; Mice; Mice, Inbred Strains; Muscle, Smooth; Nephritis, Interstitial; Nephrotic Syndrome

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Fibronectins; Kidney Tubules; Mice; Mice, Inbred Strains; Nephritis, Interstitial; Nephrosis; Platelet-Derived Growth Factor

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Base Sequence; Collagen; Enalapril; Female; Fibroblasts; Fibrosis; Glycoproteins; Immunohistochemistry; Macrophages; Molecular Sequence Data; Muscle, Smooth; Nephritis, Interstitial; Polymerase Chain Reaction; Protease Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Ureteral Obstruction

TCV-116 and enalapril were given in two stages: (early phase) for 6 to 10 weeks to 5/6 nephrectomized (NX) rats two weeks after nephrectomy, 12-week-old Wistar fatty (WF) rats and 7-week-old spontaneously hypercholesterolemic (SHC) rats; and (late phase) for 6 to 16 weeks to 5/6 NX rats 11 weeks after nephrectomy, 27-week-old WF rats and 10-week-old SHC rats. Urinary albumin, blood pressure (BP), glomerular filtration rate (GFR) and renal histology were examined. In the early phase, both agents inhibited proteinuria and tended to inhibit glomerulosclerosis. TCV-116 also inhibited interstitial inflammation. The antiproteinuric effects did not necessarily correlate with the BP-lowering effects. In the late phase, both agents showed equal antiproteinuric and antihypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubulointerstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunction, but enalapril had little effect on these parameters. In the SHC rats, TCV-116 inhibited renal tubulointerstitial inflammation and glomerulosclerosis, but enalapril inhibited only glomerulosclerosis. After drug administration, there was a positive correlation between proteinuria and BP, and a negative correlation between the severity of tissue damage and GFR, but not BP. These findings suggest that initial BP-independent tubulointerstitial inflammation may enhance glomerulosclerosis in the late phase, and TCV-116 might prevent the development of glomerulosclerosis through inhibition of angiotensin II-mediated tubulointerstitial damage in these models.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Enalapril; Glomerular Filtration Rate; Glomerulonephritis; Hypercholesterolemia; Kidney Glomerulus; Nephritis, Interstitial; Prodrugs; Proteinuria; Rats; Rats, Wistar; Tetrazoles

Topics: Acute Disease; Acute Kidney Injury; Anti-Bacterial Agents; Antihypertensive Agents; Enalapril; Erythromycin; Glomerulonephritis, IGA; Humans; Hypertension; Male; Middle Aged; Nephritis, Interstitial

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney (OBK). In this study we report that a specific angiotensin II (Ang II) receptor antagonists, SC-51316, ameliorates the expansion of the renal cortical interstitium in the OBK of the rat at five days of UUO. This is similar to the effect of an angiotensin converting enzyme (ACE) inhibitor, enalapril. SC-51316 (20 mg/liter in the drinking water) or enalapril (200 mg/liter in the drinking water) was administered beginning 24 hours before UUO and continued through five days after UUO. The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method, and monocyte/macrophage infiltration, alpha smooth muscle actin (alpha SMA), proliferating cell nuclear antigen (PCNA), and collagen type IV (collagen IV) protein deposition were examined histologically using specific antibodies. We also examined the mRNA levels of transforming growth factor beta 1 (TGF-beta 1) and collagen IV by reverse transcription polymerase chain reaction. In untreated rats with UUO, Vv was remarkably expanded; collagen IV and alpha SMA protein deposition in the interstitium and PCNA labeling of nuclei were increased. These changes were significantly ameliorated by administration of an ACE inhibitor or an Ang II receptor antagonist. A monocyte/macrophage infiltration was evident in the OBK of untreated or Ang II receptor antagonist treated rats but was greatly reduced in the OBK of rats given enalapril. Increased expression of TGF-beta 1 mRNA and collagen IV mRNA was blunted (40 to 75%) by the administration of Ang II receptor antagonist or enalapril. The Ang II receptor antagonist or the ACE inhibitor did not affect the contralateral kidney of rats with UUO or the control kidney of normal rats. This study indicates that the renin-angiotensin system has a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive nephropathy. The tubulointerstitial fibrosis of obstructive nephropathy is most likely mediated by an increased level of Ang II in renal tissue.

Topics: Actins; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Collagen; Disease Models, Animal; Enalapril; Female; Immunohistochemistry; Monocytes; Nephritis, Interstitial; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Triazoles; Ureteral Obstruction

The aim of this study was to determine whether or not angiotensin-converting enzyme inhibitor, enalapril, could ameliorate the chronic tubulo-interstitial nephropathy (TIN) in uninephrectomized (UNx) rats. Chronic TIN(M) was induced by 2-bromoethylamine hydrobromide. Rats were assigned to five groups; control, UNx-control (UNxC), UNx treated with enalapril (UNxE), UNxMC and UNxME. Enalapril was given for 12 months as drinking water (50 mg/l). At 6 months, albuminuria in UNxE decreased significantly compared with UNxC, but without change in UNxM rats. By 12 months, although all rats in control, UNxC and UNxE remained alive, 1 and 4 rats died in UNxME and UNxMC, respectively. Albuminuria in UNxC was reduced significantly by enalapril but not in UNxM rats. Both urine volume and urine osmolality became equal to control by enalapril in UNx rats, but not in UNxM rats. Serum cholesterol levels were normalized by enalapril in UNx rats, but not in UNxM rats. Levels of serum creatinine and blood urea nitrogen were invariably higher in UNxM than in UNx rats, irrespective of enalapril. Glomerular sclerosis was statistically decreased by enalapril in both UNx and UNxM rats. Enalapril reduced the overall tubulo-interstitial lesions in UNx rats, but not in UNxM group. However, in UNxM rats tubular changes in medullary portion were significantly ameliorated by enalapril. These data suggest that enalapril has a beneficial effect on chronic TIN in this model.

Topics: Albuminuria; Animals; Cholesterol; Chronic Disease; Drug Evaluation, Preclinical; Enalapril; Kidney; Male; Models, Biological; Nephritis, Interstitial; Osmolar Concentration; Rats; Rats, Wistar; Serum Albumin; Time Factors; Triglycerides

The relationship between tubulointerstitial nephritis and proteinuria was characterized in experimental nephrosis in rats. In one group, proteinuria induced by aminonucleoside of puromycin (PAN) was reduced by using an 8% protein diet and adding the angiotensin I-converting enzyme (ACE) inhibitor enalapril to the drinking water. Two control groups were injected with saline and PAN, respectively, and fed a 27% protein diet. The first group had significantly reduced albuminuria and a definite attenuation of tubular cell injury. There was a strong positive correlation between the number of interstitial macrophages and albuminuria. The beneficial effect was reproduced by dietary-protein restriction alone, whereas ACE inhibition alone had an insignificant effect on the degree of proteinuria. Depletion of circulating T lymphocytes in one group of nephrotic rats eliminated interstitial lymphocytes but did not affect interstitial macrophage influx. Inhibition of the in situ proliferation of resident interstitial macrophages by unilateral kidney irradiation failed to change the intensity of the macrophage infiltration. Treatment of rats with sodium maleate produced proximal tubular cell toxicity but interstitial inflammation did not develop, suggesting that the latter is not a nonspecific response to tubular injury. These studies demonstrate a strong relationship between tubulointerstitial nephritis and the severity of proteinuria in experimental nephrosis.

Topics: Acute Disease; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Division; Dietary Proteins; Disease Models, Animal; Enalapril; Female; Kidney; Lymphocyte Depletion; Macrophages; Maleates; Nephritis, Interstitial; Nephrotic Syndrome; Proteinuria; Puromycin; Rats; Rats, Inbred Lew