title: Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity.
abstract: Chronic treatment with cyclosporine (CsA) is limited not only by glomerular hypofiltration but also by structural damage. The pathogenesis of these nephrotoxicities was studied in a model of chronic CsA-induced renal damage. Salt-depleted rats were treated with daily CsA (15 mg/kg sc) for approximately 3 weeks, at which time renal function was measured and kidneys were harvested for morphologic assessment. A separate group of rats (CsA + BQ123) were identically treated with CsA but in addition also received simultaneous treatment with a specific endothelin A (EtA) receptor antagonist, BQ123, which was continuously delivered via sc osmotic pump (1 mg/kg per hour) and maintained throughout the study. Chronic CsA treatment caused profound functional and structural damage, although blood pressure was normal (102 +/- 6 mm Hg); GFR was 0.05 +/- 0.02 mL/min per 100 g body wt, and RPF was 0.15 +/- 0.06/100 g body wt. Renal injury was scored on a scale of 0 to 4 and showed dilation/vacuolization of 1.07 +/- 0.29 and tubulointerstitial fibrosis of 0.78 +/- 0.17. Arteriolopathy was present in 78 +/- 4% of arterioles. Chronic antagonism of the EtA receptor preserved renal function: GFR was 0.15 +/- 0.03 mL/min per 100 g body wt, and RPF was 0.32 +/- 0.08/100 g body wt (P < 0.05 for GFR versus CsA). Blood pressure was not affected: 104 +/- 8 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232-2584, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Hunley
authors.forename: A
authors.initials: A
authors.lastname: Fogo
authors.forename: S
authors.initials: S
authors.lastname: Iwasaki
authors.forename: V
authors.initials: V
authors.lastname: Kon
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D065128:Endothelin Receptor Antagonists; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D013997:Time Factors
chemical_list: D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D016572:Cyclosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)