endothelin-1 and Nephrosis

BackgroundThe pathogenesis of idiopathic nephrotic syndrome (INS) remains unclear, although recent studies suggest endothelin 1 (ET-1) and CD80 of podocytes are involved. We investigated the potential of antagonist to ET-1 receptor type A (ETRA) as therapeutic agent through the suppression of CD80 in a rat model of INS.MethodsPuromycin aminonucleoside (PAN) was injected to Wister rats to induce proteinuria: some were treated with ETRA antagonist and others were treated with 0.5% methylcellulose. Blood and tissue samples were collected. Quantitative PCR was used to determine the expression of Toll-like receptor-3 (TLR-3), nuclear factor-κB (NF-κB), CD80, talin, ETRA, and ET-1 in the kidney. To confirm the level of CD80 protein expression, immunofluorescence staining and western blot analysis of the renal tissue were performed.ResultsAmount of proteinuria in the treatment group was significantly lower than the other groups. The same-day body weight, serum creatinine values, and blood pressure were not significantly different. ETRA antagonist restores podocyte foot process effacement as well as the aberrant expression of TLR-3, nuclear factor-κB (NF-κB), and CD80 in PAN-injured kidneys.ConclusionsThe ETRA antagonist may be promising drug for INS as it showed an antiproteinuric effect. Its action was considered to be through suppression of CD80 expression on podocytes.

Topics: Animals; B7-1 Antigen; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Kidney; Kidney Diseases; Kidney Glomerulus; Nephrosis; Nephrotic Syndrome; NF-kappa B; Phenylpropionates; Podocytes; Proteinuria; Puromycin Aminonucleoside; Pyridazines; Rats; Rats, Wistar; Receptor, Endothelin A; Toll-Like Receptor 3

Nephrotic syndrome induced by adriamycin (ADR) is an experimental model of glomerulosclerosis in humans. The AT(1) receptor for angiotensin II (Ang II) is involved in the renal expression of the nuclear factor-kappa B (NF-ΚB) during this nephrosis. NF-ΚB is a transcription factor for proinflammatory effects of Ang II; however, there is no information about the role of this receptor in the renal proinflammatory events in ADR nephrosis.. To determine the role of Ang II in ADR nephrosis, Sprague-Dawley rats were treated with ADR (6 mg/kg iv). One ADR group received oral losartan treatment (15 mg/kg gavage) 3 days before ADR injection and then daily for 4 weeks, and the other group water. Animals were sacrificed at week 4 and renal macrophage infiltration, ICAM-1, superoxide anion (O(2(-))) and Ang II expressions were analysed by indirect immunofluorescence and histochemical techniques.. ADR rats showed increased expression of ICAM-1, Ang II, O(2(-)) and macrophage infiltration, events that were diminished by losartan treatment. Ang II expression remained unaltered after antagonist treatment. Proteinuria was reduced after 3 weeks of treatment.. These data suggest that Ang II plays a role in the inflammatory events during ADR-induced nephrosis, probably mediated by AT(1) receptors.

Topics: Angiotensin II; Animals; Cholesterol; Disease Models, Animal; Doxorubicin; Endothelin-1; Fluorescent Antibody Technique; Inflammation; Inflammation Mediators; Kidney; Losartan; Male; Nephrosis; Proteinuria; Rats; Rats, Sprague-Dawley; Time Factors; Triglycerides; Weight Gain

We previously reported that mRNA levels for extracellular matrix (ECM) components and endothelin (ET)-1 are upregulated in glomeruli of puromycin aminonucleoside (PAN) nephrosis. Angiotensin-converting enzyme (ACE) inhibitors are effective in experimental models of renal injury, including PAN nephrosis. This study was designed to assess whether the glomerular expression of mRNA for ECM components, ET-1, metalloproteinases (MMP), and a tissue inhibitor of metalloproteinases (TIMP) is modulated by a specific endothelin receptor A antagonist (FR139317) or angiotensin-converting enzyme inhibitor (enalapril) in PAN-injected rats.. Animals were divided into six groups. Group 1 consisted of PAN-injected rats given no treatment. In group 2, PAN-injected rats were given enalapril 35 mg/l. In group 3, PAN-injected rats were given an intraperitoneal injection of FR139317. Group 4 consisted of saline-injected rats given no treatment. In group 5, saline-injected rats were given enalapril. In group 6, saline-injected rats were given FR139317. We prepared glomerular RNA and performed Northern blot analysis in all groups.. In PAN nephrosis, glomerular mRNA levels for alpha 1 (IV) collagen chain, laminin B1 and B2 chains, ET-1, MMP-2 and TIMP-1 increased at the peak of proteinuria on day 8 and then decreased to the control level by day 20, whereas those for alpha 1 (I) and alpha 1 (III) collagen chains, MMP-1, MMP-3 and GAPDH showed little change in PAN nephrosis throughout the experimental periods. In contrast, mRNA levels for heparan sulphate proteoglycan (HSPG) decreased on day 8 and then increased to the control level by day 20. Both enalapril and FR139317 attenuated the increases in mRNA levels for alpha 1 (IV) collagen chain (P < 0.01), laminin chains (P < 0.01), and ET-1 (P < 0.01), and attenuated the decreases in mRNA levels for HSPG (P < 0.01) in glomeruli of PAN-injected rats. Enalapril had little effect on increased glomerular mRNA levels for MMP-2 and TIMP-1 in PAN nephrosis, whereas FR139317 attenuated the increases in glomerular mRNA levels for MMP-2 (P < 0.01) and TIMP-1 (P < 0.01).. These data suggest that the beneficial effects of enalapril and FR139317 may be related to modulation of glomerular mRNA expression of ECM components and ET-1 and that these agents may follow a different mechanism in regulating the glomerular mRNA expression for MMP-2 and TIMP-1 in PAN nephrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Extracellular Matrix; Gelatinases; Glycoproteins; Indoles; Kidney Glomerulus; Male; Matrix Metalloproteinase 2; Metalloendopeptidases; Nephrosis; Protease Inhibitors; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Tissue Inhibitor of Metalloproteinases

1. The aim of the study was to visualize endothelin-1 (ET-1)-mediated constriction in renal vessels of cortical and juxtamedullary glomeruli in the split hydronephrotic rat kidney in vivo and to functionally characterize the ET receptor subtypes involved. 2. ET-1 (10(-9) M) constricted preglomerular vessels (by 6-18%) and efferent arterioles (by 11-13%), and decreased glomerular blood flow (GBF, by 55%) of cortical and juxtamedullary glomeruli. 3. The ETA antagonist BQ-123 (10(-6) M), as well as the ETB antagonist BQ-788 (2 x 10(-7) M) and IRL 1038 (10(-6) M), shifted the concentration-response curve of GBF for ET-1 to the right by one order of magnitude. While BQ-123 antagonized ET-1 constriction only in preglomerular vessels, BQ-788 and IRL 1038 were effective both in preglomerular vessels and efferent arterioles. 4. The ETB agonist IRL 1620 (10(-8) M) reduced GBF by 50% and constricted efferent arterioles (by 20-33%) about two times more than preglomerular vessels (by 6-14%). 5. Our results suggest that in renal cortical and juxtamedullary vessels of rats, ET-1-induced preglomerular vasoconstriction is mediated by ETA and ETB receptors, while efferent vasoconstriction is predominantly mediated by ETB receptors, which might have important consequences for the regulation of glomerular filtration pressure by ET.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Glomerular Filtration Rate; Kidney; Kidney Glomerulus; Microcirculation; Nephrosis; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction