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Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis
Gopala K Rangan1, Jason D Coombes
1Centre 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
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.
Conclusion:
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.
Insights
Sirolimus (a target of rapamycin inhibitor) reduced kidney enlargement and renal scarring in a rat model of focal segmental glomerulosclerosis. These findings suggest sirolimus offers renoprotective effects in early-stage chronic kidney injury.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Focal segmental glomerulosclerosis (FSGS) involves glomerular hypertrophy and tubular epithelial cell (TEC) proliferation.
- Sirolimus, a target of rapamycin inhibitor, attenuates cell proliferation.
- Investigated sirolimus's effect on FSGS progression in a non-immune model.
Purpose of the Study:
- To test if sirolimus reduces glomerular hypertrophy and TEC proliferation.
- To determine if sirolimus attenuates renal scarring and dysfunction in FSGS.
- To evaluate sirolimus's renoprotective potential in early-stage chronic kidney injury.
Main Methods:
- Adult male Wistar rats with adriamycin nephropathy (AN) were used.
- Rats were divided into vehicle and sirolimus (0.1 mg/kg) treatment groups.
- Treatment administered daily via subcutaneous injection from day 14 to day 49.
Main Results:
- Sirolimus prevented kidney enlargement and attenuated glomerular capillary tuft expansion, glomerulosclerosis, and periglomerular myofibroblast accumulation.
- Sirolimus reduced tubular dilatation, TEC proliferation, and interstitial fibrosis.
- A decrease in renal cortical TGF-beta1 was observed, but inflammation markers were unaffected.
Conclusions:
- Sirolimus demonstrated anti-renotrophic properties correlated with reduced renal scarring in AN.
- The study suggests sirolimus has renoprotective effects in early FSGS.
- Sirolimus may be beneficial when administered during the early stages of chronic renal injury patterns like FSGS.
