Insulin resistance (IR) seemingly plays a role in chronic kidney disease (CKD). The present study has elucidated the crucial interplay of oxidative stress, inflammatory, apoptotic and profibrotic signaling pathways, linking IR to CKD. The study aimed at investigating the pleiotropic nephroprotective effects of either vildagliptin or vitamin D3 in a fructose/salt-induced IR rat model, highlighting the potential molecular mechanisms underlying their action. Another interesting target was to evaluate the potential capacity of vitamin D3 to potentiate the nephroprotective effects of vildagliptin. Indeed, a state of impaired fasting glucose, IR and compensatory hyperinsulinemia, constellating with significant weight gain, atherogenic dyslipidemia and hyperuricemia was established 6 weeks after fructose/salt consumption. IR rats were then treated orally with vildagliptin (10 mg/kg/day), vitamin D3 (10 µg/kg/day) or their combination for a further 6 weeks. By the end of the 12th week, untreated IR rats displayed significantly declined renal function with parallel interwined renal oxidative stress, inflammatory, apoptotic and profibrotic changes, renal histopathological damages and markedly enhanced collagen fiber deposition. Vildagliptin and vitamin D3 reversed hyperuricemia and exerted a plethora of renal anti-oxidant, anti-inflammatory, anti-apoptotic and anti-fibrotic effects. Our study has introduced a new insight into the role of dipeptidyl peptidase-4 inhibition and silent information regulator 1/5'adenosine monophosphate-activated protein kinase activation in the nephroprotective effects of either agent, elucidating their possible crosstalk with renin angiotensin aldosterone system downregulation. Considering the superadditive renoprotective effects evoked by the combination, vitamin D3 is worth being further investigated as an additional therapeutic agent for preventing IR-induced nephropathy.

中文翻译：

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维生素D3增强维格列汀在果糖/盐诱导的胰岛素抵抗的大鼠模型中的肾脏保护作用。

胰岛素抵抗（IR）似乎在慢性肾脏疾病（CKD）中起作用。本研究阐明了氧化应激，炎症，凋亡和纤维化信号通路的关键相互作用，将IR与CKD关联。该研究旨在研究维达列汀或维生素D3在果糖/盐诱导的IR大鼠模型中的多效肾保护作用，强调了其作用的潜在分子机制。另一个有趣的目标是评估维生素D3增强维格列汀肾保护作用的潜在能力。的确，果糖/盐摄入后6周，空腹血糖，IR和代偿性高胰岛素血症受损，体重明显增加，动脉粥样硬化血脂异常和高尿酸血症。然后用维达列汀（10 mg / kg /天），维生素D3（10 µg / kg /天）或它们的组合口服IR大鼠再持续6周。到第12周结束时，未经治疗的IR大鼠表现出肾功能显着下降，并伴有相互交织的肾脏氧化应激，炎症，凋亡和纤维化改变，肾脏组织病理学损害和胶原纤维沉积明显增强。维格列汀和维生素D3可以逆转高尿酸血症，并发挥大量的肾脏抗氧化，抗炎，抗凋亡和抗纤维化作用。我们的研究对二肽基肽酶-4的抑制作用和沉默信息调节剂1/5'磷酸腺苷单磷酸激活的蛋白激酶活化在任何一种药物的肾保护作用中的作用有了新的认识，阐明了它们与肾素，血管紧张素，醛固酮系统下调的可能的串扰。考虑到该组合物具有的超加性肾保护作用，值得进一步研究维生素D3作为预防IR引起的肾病的另一种治疗剂。