Evaluation the Cotherapeutic Ginkgo Biloba Plus Metformin against the Methylglyoxal-Induced Renal Tubular Lipotoxicity and Cellular Senescence in Cell Cycle via Srebp and Ppar Pathways

The diabetic kidneys are prone to progress to glomerulosclerosis and tubulointerstitial fibrosis. Although glomerulopathy is popularly observed in diabetic patients, the pathological changes occurring in the proximal convoluted tubules and interstitium are considered as the primary pathological foci of the diabetic renal disease. Methylglyoxal is one of reactive dicarbonyl species during glycolysis, which usually is raised to unusually high level in diabetic patients. The cell senescence and cell cycle arrest are closely related to the renal cell proliferation and hyperplasia at the early stage of DM, which has been considered to be related to hyperfiltration, implicating the effective prevention of the development of late stage DM by reverting the senescence of the glomerular tubules. Previous studies have mentioned that renal lipotoxicity through the transcription factors SREBPs and PPARs is related with the progression of renal lipotoxicity and CKD. Thus it is believed that worsening kidney can be mitigated by targeting renal lipid accumulation and metabolic dysregulation at the early stage. However the documented relationship between the renal lipotoxicity and the cell senescence is still lacking. Ginkgo biloba extract (GBE) is one of few nutraceutics having been approved by the Ministry of Health and Welfare. It has been listed as one of the adjuvant medicines conditionally supported by the national insurance. Accumulating literature regarding GBE had been associated with the renal diseases and in reality has showed promising in vivo effects as renal protective agents. Seldom researches had focused on the mechanistic signaling related with cell senescence, in particular, the in vitro studies. Metformin has long been used as the first line clinical antidiabetic medication, the drawback of which is inapplicable to patients with renal dysfunction. The preliminary test in our laboratory has revealed promising effect of the co-therapy of GBE with Metformin toward the renal lipotoxicity and cellular senescence. Considering there already have been immense patients having used GBE adjuvant with the clinical medicine for treating DM hyperlipidemia, we propose that GBE may alleviate the lipid metabolism in DM and the associated renal lipotoxicity. And above all, we expect that the co-therapy of GBE with Metformin may further highlight the clinical outcome.