Effects of Apigenin on mesangial gata-3 expression and PDGFR-B/NFxB signal pathway in experimental model of diabetic nephropathy

Diabetic nephropathy (DN) is the most common microvascular complication of diabetes and is also the most common cause of end-stage renal disease (ESRD) requiring dialysis. Despite the development of various treatment strategies, an effective and functional treatment protocol for DN has not yet been found. Numerous studies have shown that flavonoids, which have multiple protective effects, can alleviate DN. Apigenin, a flavonoid found abundantly in some fruits and vegetables, is known to exhibit pharmacological effects such as anti-inflammatory, antioxidant and anticancer properties. Traditionally considered a non-immune disease, accumulating evidence now suggests that immunologic and inflammatory mechanisms play a significant role in the pathology of DN. Mesangial cell proliferation induced by hyperglycemia associated with DM is a hallmark feature of DN, and understanding DN and the regulation of this mechanism is clinically important. Therefore, in this study, for the first time, the effect of Apigenin on mesangial cell proliferation in an experimental DN model induced by Streptozotosin (STZ) injection was evaluated through GATA3, PDGFR-β and NFκB expressions. Forty-two male Wistar rats were divided randomly into seven groups as intact control group with no diabetes induction or any intervention, sham group receiving only physiological saline for 4 weeks, Api group receiving Apigenin for 4 weeks without diabetes induction, PDTC group receiving PDTC for 4 weeks without diabetes induction, DN group with a single dose of STZ injection to induce DN, DN+Api group receiving Apigenin for 4 weeks starting from the third day of diabetes induction, and DN+PDTC group receiving PDTC 4 hours before sacrifice after DN induction. Kidney tissue and blood serum samples from all groups were evaluated using light and electron microscopy, immunohistochemical, molecular biological, and biochemical methods. It was found that GATA3, PDGFR-β and NF-κB expressions were upregulated in DN group, while their expression levels were significantly decreased in DN+Api and DN+PDTC groups. Microscopic examinations revealed diffuse and nodular glomerulosclerosis due to mesangial proliferation, fibrosis and severe degenerative changes of tubular cells and renal corpuscles in DN group, whereas a reduction in renal damage related to DN was observed in Apigenin treatment group. Interestingly, in our study, downregulation of PDGFR-β expression with PDTC compared to the group treated with Apigenin suggested an effective feedback mechanism between PDGFR-β and NFκB. Taken together, the findings suggest that GATA3 and NF-κB, upregulated via PDGFR-β/NF-κB in DN, are downregulated with Apigenin treatment, thereby suppressing mesangial proliferation and inflammation. Apigenin treatment effectively reduced glomerulosclerosis and fibrosis, thus facilitating renal recovery. Therefore, it is concluded that Apigenin, as an anti-glomerulosclerotic therapeutic agent, could be considered for reducing mesangial proliferation in DN.