Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis.
BACKGROUND
In this study we tested the hypothesis that sirolimus (a target of rapamycin inhibitor that attenuates intrinsic renal and immune cell proliferation) reduces glomerular hypertrophy and tubular epithelial cell (TEC) proliferation, and attenuates the progression of renal scarring and dysfunction, in a non-immune initiated model of focal segmental glomerulosclerosis (FSGS).


METHODS
Adult male Wistar rats with adriamycin nephropathy (AN) were stratified into two groups, according to proteinuria on day 12, and received either vehicle (dimethylsulphoxide) or sirolimus (0.1 mg/kg) by daily subcutaneous injection, from day 14 until day 49 (n = 8 each). Control animals were also examined (n = 3 each).


RESULTS
Sirolimus did not affect the progression of proteinuria, renal dysfunction, hypercholesterolaemia, body weight or alter intraluminal cast formation in AN. Sirolimus prevented the increase in kidney enlargement in AN, and attenuated glomerular capillary tuft expansion, glomerulosclerosis and periglomerular myofibroblast accumulation. In the tubulointerstitium, sirolimus attenuated tubular dilatation, TEC proliferation and interstitial fibrosis. This was accompanied by a reduction in renal cortical TGF-beta1, but peritubular myofibroblast accumulation and renal inflammation (glomerular and interstitial ED-1 and CD3-positive cell accumulation), were unaffected.


CONCLUSIONS
The anti-renotrophic properties of sirolimus were correlated with a reduction in renal scarring in AN. These data suggest that sirolimus has renoprotective effects when administered during the early stages of an FSGS pattern of chronic renal injury.
Rangan
Gopala K
GK
Centre for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Westmead NSW 2145, Sydney, Australia 2145. g.rangan@wmi.usyd.edu.au
Coombes
Jason D
JD
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001835:Body Weight; D049109:Cell Proliferation; D018450:Disease Progression; D004317:Doxorubicin / Q000633:toxicity; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy*; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009404:Nephrotic Syndrome / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D020123:Sirolimus