Pathways of glomerular toxicity of cyclosporine-A: an "in vitro" study.
OBJECTIVE
Knowledge of renal toxicity of cyclosporine-A (CyA) is clouded by multiple effects on different glomerular and tubular cells and on kidney and systemic hemodynamics. To focus on glomerular action of CyA we used glomeruli isolated in vitro, with the aim of dissecting the effects on recruitment of glomerular vasoconstricting systems, like endothelin-1 (ET) and angiotensins (AI and AII).


METHODS
We studied the pathways of CyA damage on pig glomeruli isolated in vitro with the technique of sieving through mesh filters of different sizes, and incubated in an appropriate culture medium. The supernatant was sampled at different time intervals to measure ET, AI and AII concentrations upon addition of ET 10(-12) or CyA 4x10(-7)M, with or without either selective endothelin receptor A (ETA) or B (ETB), or unselective ETA-ETB receptor inhibitors.


RESULTS
CyA increased ET concentration (from 9.7+/-0.3 to 11.4+/-0.4 pgxml-1, p<0.002), and the added ET released AI in the medium (from 26.6+/-4.7 to 39.1+/-4.6 pgxml-1, p<0.05) when ETB receptors were blocked. In contrast, CyA stimulated angiotensins release independent of ET receptors blockade, hence, irrespective of ET concentration in the medium, from 26.6+/-4.7 to 38.0+/-2.1 pgxml-1 for AI, p<0.05, and from 12.3+/-1.0 to 14.8+/-0.9 pgxml-1 for AII, p<0.05.


CONCLUSIONS
CyA releases ET and angiotensins independently by a direct action. Glomerular CyA toxicity might be mediated by recruitment of vasoconstricting peptides and modulated by relative ETA and ETB receptor occupancy.
Castello
L
L
Dipartimento di Scienze Mediche, Università degli Studi del Piemonte Orientale A. Avogadro, Novara, Italy.
Sainaghi
P P
PP
Bergamasco
L
L
Letizia
C
C
Bartoli
E
E
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009924:Organ Culture Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D013997:Time Factors
D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000804:Angiotensin II; C082887:PD 145065; C086539:BQ 788; D016572:Cyclosporine; D000803:Angiotensin I; C072247:cyclo(Trp-Asp-Pro-Val-Leu)