Antioxidant and Anti-inflammatory Properties of Resveratrol in Diabetic Nephropathy: A Systematic Review and Meta-analysis of Animal Studies

Abstract

Background: Accumulated experimental evidence suggests that resveratrol may have an effect on diabetic nephropathy by inhibiting inflammation and decreasing oxidative stress. However, the credibility of the evidence for this practice is unclear. Thus, we aimed to perform a systematic review and meta-analysis of animal studies to evaluate the antioxidant and anti-inflammatory properties of resveratrol when used in the treatment of diabetic nephropathy.Methods: Electronic bibliographic databases including PubMed, EMBASE, and Web of Science were searched for relevant studies. The methodological quality of animal studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Risk of Bias (SYRCLE’s RoB) tool. A meta-analysis was performed based on the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.4 software. This study was registered within International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42021293784.Results: Thirty-six qualified studies involving 726 animals were included. There was a significant association of resveratrol with the levels of blood glucose (BG), serum creatinine (Scr), blood urea nitrogen (BUN), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and interleukin-1β (IL-1β). Nevertheless, resveratrol treatment did not effectively decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, more remarkable antioxidant and hypoglycemic effects were observed in type 2 diabetic nephropathy rather than in type 1 diabetic nephropathy based on subgroup analysis.Conclusion: In this meta-analysis, resveratrol can exert its antioxidant activities by reducing the levels of MDA and recovering the activities of SOD, CAT, GSH, and GPx. With regard to pro-inflammatory cytokines, resveratrol had a positive effect on the reduction of IL-1β. However, the analysis indicated that resveratrol had no effect on IL-6 and TNF-α levels, probably because of the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory properties of resveratrol, but its relationship with the levels of some inflammatory cytokines such as IL-6 and TNF-α in animals with diabetic nephropathy needs further elucidation.

Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention

“…Clinical trial revealed that the combination of resveratrol (500 mg/d) with Losartan (12.5 mg/d) reduced the urinary albumin-creatinine ratio (UACR) (–46.4 mg/g, 95% CI: −64.5 to −28.3 vs 29.9 mg/g, 95% CI: 4.9 to 54.9; p < 0.001) and increased the activity of antioxidant enzymes [ 72 ]. A meta-analysis involving 36 animal studies demon strated that resveratrol exerted its antioxidant effects by means of reducing malondialdehyde (MDA) level and restoring activities of SOD, CAT, GSH and GPx [ 73 ]. Mechanistic studies showed that resveratrol played its therapeutic role in DKD treatment under multiple mechanisms: (1) ameliorate oxidative stress and reduce apoptosis via up-regulating AMPK expression and activity [ 74 ]; (2) regulate autophagy through overexpressing miR-18a-5p to suppress Caspase 3 [ 75 ]; (3) alleviate early-stage glomerulosclerosis via inhibiting TGF-β/Smad and ERK1/2 [ 76 ].…”

Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives

“…Thus, the main advantage of this molecule is highlighted, as it can target, at once, several pathophysiological mechanisms involved in the development and progression of DKD [ 137 , 139 ]. The impact on this condition is proven in vitro [ 140 ], in vivo [ 140 , 141 , 142 , 143 ] and also in small-sample clinical trials [ 144 , 145 ]. A recent systematic review and meta-analysis of animal studies [ 143 ] evaluating the effect of RES on DKD showed that several parameters are influenced by this molecule, including blood glucose levels and serum creatinine.…”

“…The impact on this condition is proven in vitro [ 140 ], in vivo [ 140 , 141 , 142 , 143 ] and also in small-sample clinical trials [ 144 , 145 ]. A recent systematic review and meta-analysis of animal studies [ 143 ] evaluating the effect of RES on DKD showed that several parameters are influenced by this molecule, including blood glucose levels and serum creatinine. An interesting finding was that no side effects were reported, but this outcome should be assessed with caution, as several factors could have had an impact, including dosages and a brief administration time of the drug [ 143 ].…”

“…A recent systematic review and meta-analysis of animal studies [ 143 ] evaluating the effect of RES on DKD showed that several parameters are influenced by this molecule, including blood glucose levels and serum creatinine. An interesting finding was that no side effects were reported, but this outcome should be assessed with caution, as several factors could have had an impact, including dosages and a brief administration time of the drug [ 143 ]. Li et al [ 139 ] pointed out that some of the data in the literature on RES are not as favorable, as some conflicting results appear, reinforcing the need for larger-sample studies and better assessment of the ideal dose and period of administration ( Table 1 ).…”

Identification of the molecular mechanism and candidate markers for diabetic nephropathy

“…In both animal models and DN patients, increased infiltration of circulating inflammatory mediators and immune cells into renal tissue has been observed ( 9 ). Inflammation also plays an important role in the pathogenesis of DN, such as through cell adhesion molecules, growth factors, chemokines, and proinflammatory cytokines ( 10 , 11 ). A low dose of interleukin-17A (IL-17A) can prevent DN in type 1 and type 2 diabetic models ( 12 ).…”