3.2.1. Diabetic Nephropathy

Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus [72]. Its obvious pathological changes were persistent proteinuria, changes in creatinine clearance, mesangial matrix dilatation, thickening of glomerular basement membrane, and glomerular sclerosis [73]. Numerous studies demonstrated that tea could ameliorate the pathological process of diabetic nephropathy through the antioxidant and anti-inflammatory properties [74,75]. The effects and related molecular mechanisms of tea against diabetic kidney injury are discussed below.

Green tea extract could provide a beneficial effect against long-term diabetic nephropathy via suppressing hyperglycaemia, preventing glycogen accumulation in the proximal tubules, and improving serum and urine parameters (e.g., glucose, glycosylated proteins and creatinine, and blood urea nitrogen) [70]. Green tea could defend renal tubular by reducing the urinary activity of renal tubular epithelial-cell enzymes [76]. Furthermore, green tea catechins could protect kidney function by reducing the permeability of glomerular filtration membrane through inhibiting thrombosis with lowered microsomal phospholipase A2 and regulating arachidonic acid cascade system [42]. An in vivo study also found that green tea could improve glomerular filtration and reduce the rate of creatinine increase and renal hypertrophy [77]. Further, in diabetic spontaneously hypertensive rats (SHRs), green tea prevented podocyte apoptosis and albuminuria by rising p-low-density lipoprotein receptor-related protein 6 (p-LRP6) expression and blocking glycogen synthase kinase 3 interaction with p53 (GSK3-p53) [78]. Another study also found green tea polyphenols could attenuate the urinary protein excretion and characteristic morphological changes of diabetic nephropathy by decreasing blood glucose levels [79]. Additionally, (+)–catechins might ameliorate renal dysfunction in diabetic mice by inhibiting advanced glycation end product (AGE) formation and cutting off inflammatory pathways via trapping metabolite methylglyoxal [80]. Also, green tea catechins could reduce the

oxidative damage and inflammatory reaction in the kidney by regulating the activity of 5-lipoxygenase and inhibiting the generation of superoxide radicals, oxidative proteins, lipids, and leukotriene B-4 in the kidneys of diabetic rats [81]. Moreover, green tea flavonoids could reduce ROS via three pathways, including the activation of PPARγ in the eukaryotic elongation factor-2 kinase (EEF2K) pathway by enhancing 5AMPK, the induction of nuclear factor-erythrocyte-associated factor 2 (Nrf2), by activating the Kelch-like ECH-associated protein 1-antioxidant-responsive element (Keap1-ARE) signaling, and the regulation of Mn superoxide dismutase production via Forkhead box O3 (FOXO3) -Akt pathway by increasing sirtuin-1 [82]. In addition, green tea catechins, especially EGCG and epicatechin gallate (ECG), could improve the thickening of the basement membrane by relieving the damage of matrix metalloproteinase (MMP), which could degrade extracellular matrix and fibrosis, finally alleviating diabetic nephropathy [83–85].

Besides green tea, other types of tea also show protective e ffects against diabetic nephropathy. Pu-erh tea could ameliorate diabetic nephropathy by decreasing RAGE expression and glomerular IgG deposit through inhibiting AGE accumulation [73]. Cuiyu tea (a dark tea) polypeptides were reported to stimulate the PKCζ/JNK/nuclear factor-κB (NF-κB)/THFα/iNOS, advanced glycation end products (AGEs)/RAGE/TGF-1 pathway, up-regulate the expression of podocin in glomeruli, and decrease the release of proinflammatory cytokines, thereby ameliorating diabetic nephropathy [86]. Further, oolong tea polysaccharides could reduce renal tissue inflammation and improve the glomerular vascular permeability of glutathione peroxidase (GSH-PX) by enhancing the activity of superoxide dismutase and GSH-PX [87]. In general, tea exhibits good e ffects against diabetic nephropathy in vitro and in vivo.
