The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats.
OBJECTIVE
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and mammalian target of rapamycin (mTOR) inhibitors share mechanisms concerning cell growth and reduction of extracellular matrix accumulation. The purpose of this study was to evaluate the potential synergistic effect of this combination on diabetic kidney disease in rats.


METHODS
Diabetes was induced by streptozotocin in 42 male Sprague-Dawley rats. Sixteen weeks after diabetes induction, animals were divided into four groups: diabetic animals without intervention (D), diabetic animals with administration of sirolimus (D+SRL), diabetic animals with administration of rosiglitazone (D+RGT), and diabetic animals with administration of sirolimus and rosiglitazone (D+SRL+RGT).


RESULTS
At a 30-day follow up, diabetic rats showed higher kidney weight, mean glomerular volume, mesangial expansion and albuminuria compared with non-diabetic rats. mTOR downstream proteins, p-T389-S6K and p-T37/46-4EBP1, were higher in diabetic than non-diabetic kidneys, whereas p-S473-AKT was not, suggesting that hyperglycemia mainly activated the mTORC1 pathway in vivo. Moreover, the catalytic subunit of protein phosphatase 2A (PP2Ac) was down-regulated in the diabetic kidney. Sirolimus inhibited the mTORC1 pathway, while the PPAR-gamma agonist rosiglitazone enhanced PP2Ac and reduced p70S6K. Both drugs were associated with a reduction in albuminuria, renal enlargement and mesangial expansion, but without any improvement in glycemic control. Sirolimus and rosiglitazone in combination down-regulated the mTORC1 pathway and over-activated PP2Ac in diabetic kidney. This effect may account for the synergistic reduction of renal hypertrophy, albuminuria and renal TGF-beta1 observed in diabetic rats treated with SRL+RGT.


CONCLUSIONS
The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.
Flaquer
Maria
M
Departament de Ciències Fisiològiques II, IDIBELL, University of Barcelona, Bellvitge Hospital, Spain.
Lloberas
Núria
N
Franquesa
Marcella
M
Torras
Joan
J
Vidal
August
A
Rosa
Jose Luis
JL
Herrero-Fresneda
Immaculada
I
Grinyó
Josep M
JM
Cruzado
Josep M
JM
D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000187:drug effects
C519510:Crtc1 protein, rat; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D045162:Thiazolidinediones; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000077154:Rosiglitazone; D054648:Protein Phosphatase 2; D020123:Sirolimus