The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats.

Abstract

AIMS:

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.

MAIN 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).

KEY FINDINGS:

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.

SIGNIFICANCE:

The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.

• Authors: Maria Flaquer, Núria Lloberas, Marcella Franquesa, Joan Torras, August Vidal, Jose Luis Rosa, Immaculada Herrero-Fresneda, Josep M Grinyó, Josep M Cruzado
• Journal: Life sciences (Life Sci) Vol. 87 Issue 5-6 Pg. 147-53 (Jul 31 2010) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 20600147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Crtc1 protein, rat
• Hypoglycemic Agents
• Immunosuppressive Agents
• Thiazolidinediones
• Transcription Factors
• Transforming Growth Factor beta1
• Rosiglitazone
• Protein Phosphatase 2
• Sirolimus

Topics

• Albuminuria (drug therapy)
• Animals
• Diabetes Mellitus, Experimental (complications)
• Diabetic Nephropathies (drug therapy, physiopathology)
• Down-Regulation (drug effects)
• Drug Synergism
• Drug Therapy, Combination
• Hypoglycemic Agents (administration & dosage, pharmacology)
• Immunosuppressive Agents (administration & dosage, pharmacology)
• Male
• Protein Phosphatase 2 (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Rosiglitazone
• Sirolimus (administration & dosage, pharmacology)
• Thiazolidinediones (administration & dosage, pharmacology)
• Transcription Factors (genetics, metabolism)
• Transforming Growth Factor beta1 (drug effects)