lisinopril and Ureteral-Obstruction

In this study, it was aimed to investigate apoptosis in renal injury and the effect of lisinopril in rat model, which constitute unilateral ureteral obstruction. The retroperitoneal ureter was ligated with a 4.0 silk for the experimental model of ureteral obstruction in Wistar albino rats. Untreated group (n = 20) received no treatment. For the lisinopril-treated group (n = 20), 20 mg/kg/day of drug was given orally. Ultrastructural differences were analyzed using electron microscopic technique; apoptotic distribution was analyzed using the TUNEL method. After electron microscopic evaluation, on the 4th and 14th day in the untreated group, edema in the glomeruli, loss of microvillus and apoptotic cells in proximal tubule cells and sclerosis in the glomeruli were detected. On the 4th day in the lisinopril-treated group, the kidney was ultrastructurally normal and a less number of apoptotic cells were only observed on the 14th day. On light microscopic examination on the 4th and 14th day in the untreated group, while the glomeruli were normal in structure, the boundary of the proximal tubule was disrupted and some picnotic cells in both the proximal and collecting tubules were observed. In both 4th and 14th day of the lisinopril-treated group, kidney showed normal structure, although in some places picnotic cells in the collecting tubules were observed. In conclusion, lisinopril was effective and it may prevent early renal damage in the direct obstruction model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; In Situ Nick-End Labeling; Kidney; Lisinopril; Male; Rats; Rats, Wistar; Ureteral Obstruction

Unilateral ureteral obstruction (UUO) is a well established experimental model of renal injury leading to interstitial fibrosis. The molecular and cellular mechanism(s) of interstitial fibrosis in UUO are beginning to be elucidated. In the progression of interstitial fibrosis in UUO, up-regulation of collagen synthesis is commonly observed. HSP47 is a collagen-binding stress protein and is thought to be a collagen-specific molecular chaperone, which plays a pivotal role during the biosynthesis and secretion of collagen molecules in the endoplasmic reticulum. The synthesis of HSP47 has been demonstrated to always parallel that of collagen in physiological and pathophysiological conditions. It is well recognized that renin-angiotensin system (RAS) is enhanced in the setting of UUO and that enhanced RAS has been implicated in the pathogenesis of interstitial fibrosis in the obstructed kidneys.. To investigate the role of HSP47 in the progression of interstitial fibrosis in mouse UUO, the expression of HSP47 was examined by Northern blotting, immunohistochemistry and in situ hybridization in the obstructed kidneys. To test the possible involvement of enhanced RAS on the HSP47 expression, we examined the effects of lisinopril, an angiotensin converting enzyme inhibitor, on interstitial fibrosis. HSP47 and type I collagen mRNA expression.. By Northern blot analysis, HSP47 mRNA was significantly up-regulated at 12 hours (about twice that of sham operated kidneys) after the onset of ureteral obstruction, further increased and stayed at the increased level until seven days (about 8 times that of sham operated kidneys). HSP47 mRNA and protein expression were observed in the periglomerular and peritubular interstitial regions of the obstructed kidneys. Distribution of smooth muscle alpha actin and type I collagen immunoreactivity were similar to the HSP47 distribution pattern, suggesting that HSP47 was up-regulated in the myofibroblasts. Lisinopril ameliorated the expansion of cortical interstitium in the obstructed kidneys at four and seven days after ureteral obstruction. HSP47 mRNA expression was suppressed at four and seven days, whereas type I collagen mRNA was suppressed only at seven days after the onset of ureteral obstruction.. These results demonstrate the early and persistent up-regulation of HSP47 during the progression of interstitial fibrosis in mouse UUO kidneys, and further suggest the potential role of HSP47 in the pathogenesis of interstitial fibrosis in the obstructed kidneys. Partial suppression of HSP47 mRNA expression by lisinopril at day 4 and day 7 after ureteral obstruction suggests that there are other immediate trigger(s) that induce the HSP47 mRNA expression. Identification of the molecular mechanism of HSP47 induction during UUO may give an insight into the novel aspects of the molecular pathophysiology of interstitial fibrosis in obstructive nephropathy.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; Fibrosis; Gene Expression; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Immunoenzyme Techniques; In Situ Hybridization; Kidney; Lisinopril; Male; Mice; Mice, Inbred C3H; Renin; Renin-Angiotensin System; RNA, Messenger; Ureteral Obstruction

We have shown that acute (24-hr) unilateral ureteral obstruction (UUO) induces the genes encoding for renin, in juxtaglomerular apparatuses and in tubules, for angiotensin converting enzyme in vascular endothelial cells, and for angiotensinogen in perivascular fat. These molecular changes occur in temporal association to marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR), suggesting that angiotensin II (Ang II) is at least partly responsible for the renal vasoconstriction. We tested the hypothesis that down-regulation of the Ang II type-1 receptor (AT1-R) gene occurs in UUO in response to Ang II, by examining the effects of an ACE inhibitor [lisinopril (Li), 5 mg/kg/day] and of the specific nonpeptidic AT1-R blocker, losartan (Lo) (10 mg/kg/day). UUO or sham operated (which included manipulation but not obstruction of the ureter) rats (S) were studied. Northern blot analysis of the steady state concentration of AT1-R mRNA corrected for GAPDH mRNA showed a marked decrease in receptor expression (-77%, N = 4, P < 0.01) in the obstructed kidney (UUO) compared to S; sham diminished gene expression modestly compared to the contralateral kidneys (C) of UUO. In situ hybridization for AT1-R mRNA also showed diminished expression in UUO compared to C kidneys (N = 4). Treatment of UUO rats (N = 4) with Lo increased AT1-R mRNA five times above the levels in UUO rats receiving vehicle; the increase induced by Li was 50% that of Lo; S (N = 4) and C (N = 4) did not change. Losartan, but not vehicle treatment increased RBF (sixfold) and GFR (fivefold) in the UUO kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Down-Regulation; Gene Expression Regulation; Imidazoles; Kidney; Lisinopril; Losartan; Male; Rats; Rats, Wistar; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Ureteral Obstruction

This study was designed to evaluate renal functional reserve (RFR) in obstructive nephropathy using amino acid loading and the effect of angiotensin converting enzyme (ACE) inhibitor on RFR. We divided 24 rabbits into 4 groups, consisting of a control, 6-hours-bilateral ureteral obstruction (BUO), 24-hour BUO and 24-hour BUO pretreated with ACE inhibitor. Following the ligation of the bilateral ureters at the vesicoureteral junction, a unilateral ureter was released after a 6-hour or 24-hour duration in the obstructive groups. We measured RFR and renal vascular resistance after releasing a unilateral ureter in BUO. The baseline GFR values in the 6-hour and 24-hour BUO groups were significantly lower than that in the control. RFR were 0.34 + 0.04 ml/min/kg (control), 0.10 + 0.03 (6-hour BUO), 0.01 + 0.03 (24-hour BUO) and 0.10 + 0.01 (ACE inhibitor), respectively. RFR in the 6-hour BUO group was well preserved compared with that in the 24-hour BUO group. Pretreatment with ACE inhibitor in the 24-hour BUO group enhanced RFR to the extent of 6-hour BUO. Our results demonstrated that angiotensin II plays an important role in decreased GFR with obstructive nephropathy. Moreover, the present data suggested that evaluation of RFR might play a key role in the recovery of the post-obstructive renal function.

Topics: Animals; Glomerular Filtration Rate; Kidney; Kidney Diseases; Lisinopril; Rabbits; Renal Circulation; Ureteral Obstruction; Vascular Resistance

The effect of 24-hour unilateral ureteral obstruction (UUO) on the expression and regulation of the renin-angiotensin system (RAS) in rats and of pretreatment with lisinopril (5 mg/kg/day) or the AT1-R inhibitor, losartan, (10 mg/kg/day) on renal hemodynamics was evaluated. Both drugs improved the post-obstructed kidney (POK) renal hemodynamics, lowered MAP, and normalized eicosanoid excretion by the POK. Cortex and medulla POK:CK ratio of relative density R mRNA was approximately 3.5 for both. Sham, POK, and CK showed renin immunoreactivity and R mRNA exclusively in juxtaglomerular position. In addition, in POK renin was expressed in mesangial cells, along greater lengths of afferent arterioles and in dilated distal tubules and loops of Henle. In situ hybridization revealed that approximately 20% more glomeruli in POK than CK overexpressed R mRNA. Blood vessels of POK consistently showed greater ACE and Ao mRNA expression than CK. Overexpression of the genes coding for members of the RAS is possibly responsible for local Ang II production which, in view of the response to CEI and AT1-R inhibitors, is at least partly responsible for the severe hemodynamic changes in UUO.

Topics: Animals; Biphenyl Compounds; Blotting, Northern; Dipeptides; Diuresis; Eicosanoids; Electrolytes; Hemodynamics; Imidazoles; Immunohistochemistry; In Situ Hybridization; Kidney; Lisinopril; Losartan; Male; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Ureteral Obstruction