Diabetes mellitus (DM), mainly characterized by recurrent hyperglycemia, had become one of the chronic disorders derived from insulin deficiency or resistance in the developed countries. As the high blood glucose level in diabetes persisted and progressed without appropriate medical care, relative secondary disorders involving atherosclerosis, retinopathy, nephropathy, neuropathy, stroke, and foot ulcer would individually develop with an insidious onset, which could eventually be life-threatening. Diabetic nephropathy (DN), the second most prevalent diabetes-associated complication inferior to cardiovascular disorders, impaired the renal function of DM patients and therefore cost appreciable medical labor and resource for DN management annually. Histologically featured by thickening of basement membrane, expansion and nodular aggregation of mesangial matrix (the Kimmelstiel-Wilson lesions) and sclerosis in glomeruli, DN could be multifactorial in the pathogenesis. In these risk factors, hyperglycemia was currently regarded as one of the leading causes in the progression of DN. Accumulating evidence also suggested the development of DN was associated with the activation of several stress-sensitive signal pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) [1–4]. Additionally, it was reported that both oxidative stress [5–8] and proinflammatory cytokines [9, 10] detrimentally accelerated the pathological process of DN. Adenosine monophosphate-activated protein kinase (AMPK), a regulator of cellular energy homeostasis, was recently identified to play an important role in DN . Decreased phosphorylation of AMPK was contributed to hyperglycemia-associated renal enlargement. Further studies indicated that suppression of AMPK activity was linked with oxidative stress  and inflammatory response . Reversion of AMPK activity could ameliorate oxidative damage  and inflammation . Thus, attention has been drawn to the modulation of AMPK signal transduction to attenuate DM-affected renal dysfunction.
Resveratrol (trans-3,4',5-trihydroxyestilbene, RSV), one naturally existing polyphenolic compound rich in grapes and several plants, was characterized as a potently free radical scavenger and antioxidative agent. Besides, RSV was pronounced to possess both cardioprotective [16–18] and antidiabetic benefits [19, 20]. A vast majority of reports also supported that RSV displayed a hypoglycemic effect on DM animal models via AMPK stimulation [21–24]. In DN studies, RSV was proved to mitigate renal dysfunction and oxidative stress in type 1 diabetic rats [5, 25].
One recent research investigated the AMPK-stimulating effect of RSV on the early stage of DN . It was also reported that RSV did not remarkably alter the messenger RNA and protein levels of inflammation-regulatory cyclooxygenase (COX) in the diabetic rat kidneys . Additionally, RSV activated NF-κB in mesangial cells under a precondition of cytokine exposure . Therefore, it still required further survey to delineate the precise mechanisms of RSV action on DN.
Considering the hypoglycemic, antioxidative, inflammatory modulation and AMPK-up-regulating effects of RSV on type 1 DM, we designed this study to realize the therapeutic effects and associated mechanisms of RSV on streptozotocin (STZ)-induced DM rats. The oxidative stress, proinflammatory cytokines, and several cellular stress-activated signal pathways were simultaneously evaluated in diabetic rats. Our results show the renoprotective effects of RSV may contribute by its antioxidative and AMPK-up-regulating abilities and, to our interest, found that RSV significantly augmented inflammatory response in diabetic kidney by elevating several cytokines like tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), despite its ameliorative effect on IL-1β cytokine level in DN.