Departament de Ciències Fisiològiques II, IDIBELL, University of Barcelona, Bellvitge Hospital, Spain.
Life Sci. 2010 Jul 31;87(5-6):147-53. doi: 10.1016/j.lfs.2010.06.004. Epub 2010 Jun 18.
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.
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).
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.
The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.
过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂和雷帕霉素靶蛋白（mTOR）抑制剂具有细胞生长和减少细胞外基质积累的共同机制。本研究的目的是评估这种联合用药对糖尿病大鼠肾脏疾病的潜在协同作用。
链脲佐菌素诱导 42 只雄性 Sprague-Dawley 大鼠糖尿病。糖尿病诱导后 16 周，动物分为四组：未干预的糖尿病动物（D）、给予西罗莫司的糖尿病动物（D+SRL）、给予罗格列酮的糖尿病动物（D+RGT）和给予西罗莫司和罗格列酮的糖尿病动物（D+SRL+RGT）。
在 30 天随访时，与非糖尿病大鼠相比，糖尿病大鼠的肾脏重量、平均肾小球体积、系膜扩张和蛋白尿均升高。与非糖尿病肾脏相比，糖尿病肾脏中的 mTOR 下游蛋白 p-T389-S6K 和 p-T37/46-4EBP1 更高，而 p-S473-AKT 则没有，提示高血糖主要在体内激活了 mTORC1 途径。此外，糖尿病肾脏中的蛋白磷酸酶 2A（PP2A）催化亚基下调。西罗莫司抑制 mTORC1 途径，而 PPAR-γ 激动剂罗格列酮增强 PP2Ac 并减少 p70S6K。两种药物均与蛋白尿、肾脏增大和系膜扩张减少相关，但对血糖控制没有任何改善。西罗莫司和罗格列酮联合使用可下调糖尿病肾脏中的 mTORC1 途径并过度激活 PP2Ac。这种作用可能解释了 SRL+RGT 治疗的糖尿病大鼠中观察到的肾脏肥大、蛋白尿和 TGF-β1 协同减少。
西罗莫司和罗格列酮联合使用对糖尿病肾病具有肾脏保护作用。
