The leukotriene B4 receptor antagonist ONO-4057 inhibits nephrotoxic serum nephritis in WKY rats.
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To evaluate the role of leukotriene B4 (LTB4) in glomerulonephritis, this study was conducted to examine whether ONO-4057, an LTB4 receptor antagonist, moderated nephritis caused by the injection of nephrotoxic serum (NTS) into Wistar-Kyoto rats. Rats were given intraperitoneal injections of ONO-4057 or phosphate-buffered saline 24 h before the injection of NTS. These rats subsequently received equal doses of ONO-4057 or phosphate-buffered saline 3 h and 1, 2, 3, 4, 5, and 6 d later. Compared with the control groups, ONO-4057 treatment significantly reduced proteinuria and hematuria, suppressed the glomerular accumulation of monocytes/macrophages, and reduced the formation of crescentic glomeruli in a dose-dependent manner. These results suggest that LTB4 is responsible for the crescentic formations and renal dysfunction associated with NTS nephritis. The LTB4 receptor antagonist ONO-4057 may thus be beneficial in the treatment of crescentic glomerulonephritis. (+info)
Late consequences of acute ischemic injury to a solitary kidney.
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The sequelae of acute ischemic injury to a solitary kidney were assessed in rats subjected to right nephrectomy and transient occlusion of the left renal artery; control rats underwent right nephrectomy alone. Incomplete recovery from ischemic injury at 2 wk (serum creatinine levels of 1.1 +/- 0.2 versus 0.5 +/- 0.1 mg/dl, P < 0.05 for ischemia versus control) was followed by deterioration of renal function at 20 wk (serum creatinine levels of 1.7 +/- 0.4 versus 0.7 +/- 0.1 mg/dl, P < 0.05 for ischemia versus control). Morphologic studies showed that impairment of function after ischemic injury was associated with widespread tubulointerstitial disease. Some tubule segments were atrophic and others exhibited cystic dilation, so that the tubular cell volume fraction was reduced (37 +/- 4 versus 53 +/- 2%, P < 0.05), while the tubular lumen and interstitial volume fractions were increased (31 +/- 4 versus 23 +/- 2% and 29 +/- 2 versus 20 +/- 1%, respectively, both P < 0.05). Many glomeruli retained open capillary loops but were no longer connected to normal tubule segments (63 +/- 8 versus 15 +/- 7% of glomeruli, P < 0.05). There was a strong inverse correlation between the prevalence of such glomeruli and the GFR at 20 wk after ischemia (r2 = 0.79, P < 0.001). Tubulointerstitial disease at that time was accompanied by proteinuria and widespread segmental glomerular tuft injury. The occurrence of similar processes in human patients could contribute to the loss of graft kidneys that suffer ischemic injury during transplantation. (+info)
The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.
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The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy. (+info)
Vascular endothelin-1 gene expression and synthesis and effect on renal type I collagen synthesis and nephroangiosclerosis during nitric oxide synthase inhibition in rats.
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BACKGROUND: The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process. METHODS AND RESULTS: Treatment of rats for 4 weeks with the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) 50 mg. kg-1. d-1 increased systolic blood pressure to 159+/-12 mm Hg. In animals treated with L-NAME, histological evaluation of renal sections revealed an increased formation of extracellular matrix (Masson's trichrome), and specifically of collagens (Sirius red). A part of this fibrosis was attributed to abnormal collagen I presence, because mRNA expression of the collagen I alpha1 chain (reverse transcription-polymerase chain reaction) and procollagen I formation (radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the renal resistance vessels of hypertensive animals. In subsequent experiments, we examined whether ET-1 was involved in activation of collagen I formation. mRNA expression (RNase protection assay) of preproET-1 and ET-1 content (radioimmunoassay) were 10-fold and 3-fold increased, respectively, in renal microvessels of rats treated with L-NAME. Interestingly, in these vessels, ET-1 (immunostaining) was colocalized with sudanophilic lesions. Bosentan, an ET receptor antagonist (20 mg. kg-1. d-1), coadministered with L-NAME canceled the increased mRNA expression and synthesis of collagen I and attenuated the severity of renal vascular lesions without affecting L-NAME-induced high blood pressure. CONCLUSIONS: These data demonstrate that ET-1 synthesis is increased in renal microvessels when NO production is suppressed. In this model of hypertension, ET-1 is a major activator of collagen I formation in renal resistance vessels and participates in the development of renal fibrosis without affecting systolic blood pressure. (+info)
Endothelial expression of VCAM-1 in experimental crescentic nephritis and effect of antibodies to very late antigen-4 or VCAM-1 on glomerular injury.
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The migration of leukocytes into glomeruli in crescentic glomerulonephritis is fundamental to pathogenesis, and offers important therapeutic opportunities. We addressed the importance of VCAM-1, and its leukocyte ligand very late antigen-4 (VLA-4), in such leukocyte migration. In a rat model of nephrotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistochemistry, was up-regulated by day 6 of nephritis. To quantify kidney endothelial VCAM-1 expression, a differential radiolabeled mAb technique was used, which demonstrated that protein expression was not up-regulated by day 2 of nephritis, but rose threefold between days 2 and 5, and remained elevated until at least day 28. An in vivo study was then performed, using blocking mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior to disease induction, and continuing until animals were sacrificed at day 7. mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerular fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no significant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal injury. Paradoxically, classical markers of macrophage activation were increased in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstrates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regulated by day 2 of nephrotoxic nephritis, and plays little part in early leukocyte influx into glomeruli. However, VLA-4 is an important mediator of glomerular injury, operating after transendothelial leukocyte migration, and presumably binding to alternate ligands within the kidney. (+info)
The concept of glomerular self-defense.
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The balance between local offense factors and defense machinery determines the fate of tissue injury: progression or resolution. In glomerular research, the most interest has been on the offensive side, for example, the roles of leukocytes, platelets, complement, cytokines, eicosanoids, and oxygen radical intermediates. There has been little focus on the defensive side, which is responsible for the attenuation and resolution of disease. The aim of this review is to address possible mechanisms of local defense that may be exerted during glomerular injury. Cytokine inhibitors, proteinase inhibitors, complement regulatory proteins, anti-inflammatory cytokines, anti-inflammatory eicosanoids, antithrombotic molecules, and extracellular matrix proteins can participate in the extracellular and/or cell surface defense. Heat shock proteins, antioxidants, protein phosphatases, and cyclin kinase inhibitors may contribute to the intracellular defense. This article outlines how the glomerulus, when faced with injurious cells or exposed to pathogenic mediators, defends itself via the intrinsic machinery that is brought into play in resident glomerular cells. (+info)
Expression of parathyroid hormone-related peptide messenger ribonucleic acid in developing kidney.
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BACKGROUND: Parathyroid hormone (PTH)-related peptide (PTHrP), originally identified as a causative agent of hypercalcemia of malignancy, has been implicated in the regulation of growth and differentiation of endochondral bone, hair follicle, and breast as an autocrine/paracrine factor. Although some experiments indicate that PTHrP works as a growth factor for primary renal cells in vitro, the role of PTHrP in the kidney in vivo is not yet known. METHODS: We examined the amounts of PTHrP and PTH/ PTHrP receptor (PTHR) mRNA in the mouse kidney developmental process by reverse transcription-polymerase chain reaction, and investigated which cells produce PTHrP and PTHR in vivo by in situ hybridization. RESULTS: We observed high levels of PTHrP mRNA during mouse kidney maturation. PTHrP mRNA was expressed in the collecting duct, urothelium of the pelvis, and immature elements in the cortex of the developing kidney, including the S-shaped body, ureteric bud, and glomerulus. However, the expression of PTHR mRNA was lower during maturation than after the completion of the maturation process, and it was not detected in the collecting duct, urothelium of the pelvis, or nephrogenic zone in embryonic day 16 or 0-day-old mouse kidneys. CONCLUSION: These findings suggest that PTHrP has a role in mouse kidney maturation or glomerular development. (+info)
BACKGROUND: Foot process effacement and condensation of the glomerular epithelial cell (GEC) cytoskeleton are manifestations of passive Heymann nephritis, a model of complement-mediated membranous nephropathy. METHODS: To study the effects of complement on the actin cytoskeleton in this model, we have used an in vitro system in which GECs are sublethally injured using a combination of complement-fixing anti-Fx1A IgG and human serum as a source of complement. We examined the effects of this injury on the organization of the cytoskeleton and focal contacts using immunohistology and immunochemistry. RESULTS: By immunofluorescence, sublethal complement-mediated injury was accompanied by a loss of actin stress fibers and focal contacts but retention of matrix-associated integrins. Full recovery was seen after 18 hours. Western blot analysis showed no change in the cellular content of the focal contact proteins. Inhibition of the calcium-dependent protease calpain did not prevent injury. In addition, cycloheximide during recovery did not inhibit the reassembly of stress fibers or focal contacts. Injury was associated with a reduction in tyrosine phosphorylation of paxillin and a currently unidentified 200 kDa protein, but inhibition of tyrosine phosphatase activity with sodium vanadate did not prevent injury. Cellular adenosine triphosphate content was significantly reduced in injured cells. CONCLUSION: These results document reversible, complement-dependent disruption of actin microfilaments and focal contacts leading to the dissociation of the cytoskeleton from matrix-attached integrins. This may explain the altered cell-matrix relationship accompanying podocyte effacement in membranous nephropathy. (+info)