Effect of sirolimus on renal ischaemia/reperfusion injury in normotensive and hypertensive rats.
Renal ischaemia/reperfusion (I/R) injury and hypertension represent major alloantigen-independent factors contributing to the development of chronic allograft nephropathy of renal allografts. In the present study, we investigated the effect of the anti-proliferative immunosuppressant, sirolimus (SIR), in a model of accelerated renal injury in hypertensive transgenic rats (TGRs). Twenty anaesthetized uninephrectomized TGRs with renin overproduction [TGR(mREN2)27] and 20 normotensive Han SD (SD) rats as genetic controls had their renal pedicles clipped for 45 min and were subsequently treated with either SIR (0.5 mg/kg per day, orally) or placebo ( n=10 in each group) for 16 weeks, after which time the kidneys were harvested for morphological and immunohistochemical analysis. High-renin hypertension aggravated the functional and structural changes induced by I/R in SD animals: both SIR-treated and untreated TGRs exhibited significantly greater proteinuria and suffered from more severe glomerulosclerosis ( P<0.01) and vasculopathy ( P<0.01), as well as compensatory renal hypertrophy ( P<0.01) and tissue TGF-beta1 expression, than both normotensive SD groups ( P<0.01). SIR-treated SD rats showed reduced proteinuria ( P<0.01), glomerulosclerosis ( P<0.01), and TGF-beta1 expression in the glomerular epithelium and proximal tubuli ( P<0.05) compared with placebo-treated SD rats. SIR-treated TGRs had significantly lower proteinuria at week 4 after I/R ( P<0.01) than placebo-treated TGRs, but there were no significant differences thereafter. Morphological patterns were similar in treated and untreated TGRs at week 16. High-renin-induced hypertension aggravated the renal injury induced by I/R. Sirolimus treatment ameliorated some late functional and morphological changes induced by I/R injury in hypertensive TGRs but, particularly, in normotensive SD rats.
Viklický
Ondrej
O
Department of Nephrology, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21 Prague, Czech Republic. ondrej.viklicky@medicon.cz
Bohmová
Radka
R
Ouyang
Nengtai
N
Honsová
Eva
E
Lodererová
Alena
A
Mandys
Václav
V
Vítko
Stefan
S
Lutz
Jens
J
Heemann
Uwe W
UW
D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D012083:Renin / Q000235:genetics; D015427:Reperfusion Injury / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D014508:Urea / Q000378:metabolism
D007166:Immunosuppressive Agents; D014508:Urea; D003404:Creatinine; D012083:Renin; D020123:Sirolimus