TABLE 1.
Nephroprotective effect of resveratrol during DN1
| Reference | Description | Outcome | Significance |
|---|---|---|---|
| Nephroprotective effect of resveratrol via modulating oxidative stress and AGEs | |||
| He et al., 2015 (42)2 | In vitro: Resveratrol (5–20 μmol/L) on high-glucose–induced EMT in renal tubular epithelial cells | Resveratrol inhibited high-glucose–induced EMT by decreasing intracellular ROS via downregulation of NOX1, NOX4, and blockade of ERK1/2 | The study suggests resveratrol is potent agent against high-glucose–induced EMT in renal tubular cells via inhibiting the NOX/ROS/ERK1/2 pathway |
| Zhang et al., 2012 (51)2 | In vitro: Resveratrol (10 μmol/L) on high-glucose–induced mesangial cell proliferation and fibronectin expression | Resveratrol prevented high-glucose–induced mesangial cell proliferation and fibronectin expressions through inhibiting JNK and NF-κB activation, NAD(P)H oxidase activity elevation, and ROS production | This study suggests the JNK/NF-κB/NOX/ROS pathway may be a novel therapeutic target of resveratrol for DN |
| Xu et al., 2012 (52)2 | In vitro: Resveratrol (10 μmol/L) against high-glucose–induced oxidative damage to mitochondria of rat mesangial cells | Resveratrol pretreatment ROS production and mitochondrial superoxide generation, as well as stimulated MnSOD activity; resveratrol also reversed the decrease in mitochondrial complex III activity in mesangial cells, which is a major source of mitochondrial oxidative stress | Resveratrol efficiently reduces oxidative stress and maintains mitochondrial function related to activating SIRT1 in glucose-treated mesangial cells |
| Wang et al., 2017 (53)2 | In vitro: Effect of resveratrol treatment (25 μmol/L) on hyperglycemia-induced oxidative stress in human kidney epithelial cells | Resveratrol increased SIRT1 deacetylase activity, decreased the expression of acetylated-FOXO3a, and inhibited oxidative stress; silencing SIRT1 blocked the resveratrol action against oxidative stress | Resveratrol modulates the SIRT1/FOXO3a pathway by increasing SIRT1 deacetylase activity, subsequently ameliorating hyperglycemia-induced renal tubular oxidative stress damage |
| Zhang et al., 2019 (54)2 | In vitro: Resveratrol (10 μmol/L) effect on high-glucose–induced oxidative stress and apoptosis in podocytes | Resveratrol attenuated high-glucose–induced ROS production and cell apoptosis, and increased the expression of SIRT1, PGC-1α, and its downstream genes NRF1 and mitochondrial transcription factor A, respiratory chain complex I and III activity, and mitochondrial membrane potential | Resveratrol ameliorates high-glucose–induced oxidative damage and apoptosis in podocytes via SIRT1/PGC-1α–mediated mitochondrial protection |
| Zhang et al., 2019 (55)2 | In vitro: Resveratrol (10 μmol/L) on high-glucose–induced oxidative stress and apoptosis in mouse podocytes and renal tubular epithelial cells | Resveratrol inhibited excessive ROS production and apoptosis, improved respiratory chain complex I and III activity, elevated mitochondrial membrane potential | The study indicates that the renoprotective effect of resveratrol in DN is via SIRT1/PGC-1α–mediated attenuation of mitochondrial oxidative stress |
| Sharma et al., 2006 (18) | In vivo: Resveratrol [5 and 10 mg/(kg · d)] on renal function and oxidative stress in diabetic rats | Resveratrol attenuated pre-DN symptoms including reduced clearance of creatinine and urea, proteinuria, and oxidative stress (elevated lipid peroxidation and decreased antioxidant enzyme activity) | The study reinforces the importance of antioxidant capacity of resveratrol against renal dysfunction in DN |
| Kitada et al., 2011 (41) | In vivo: Resveratrol treatment (0.3% with nonpurified diet) on DN in db/db mice | Resveratrol treatment reduced urinary albumin excretion and attenuated renal pathological changes in db/db mice; it also decreased mitochondrial oxidative stress and biogenesis in the kidneys | Renoprotective effect of resveratrol in DN is through improvement of oxidative stress via normalization of MnSOD function |
| Moridi et al., 2015 (47) | In vivo: Resveratrol [1, 5, 10 mg/(kg · d)] on RAGE and oxidative stress in diabetic rat kidney | Resveratrol treatment reduced malondialdehyde concentrations, plasma glucose, and expression of RAGE; the total antioxidant and insulin concentrations were significantly increased in resveratrol-treated rats | Renoprotective effect of resveratrol during DM is via attenuating oxidative stress and downregulation of RAGE expression |
| Al-Hussaini and Kilarkaje, 2018 (48) | In vivo: Resveratrol [5 mg/(kg · d)] on diabetes-induced oxidative DNA damage and AGEs in rat kidneys | Resveratrol reduced renal hypertrophy and structural changes such as tubular atrophy, mesangial expansion or shrinkage, diffuse glomerulonephritis, and fibrosis in diabetic rats; it also reduced AGE accumulation, oxidative stress, and DNA damage | The study suggests that resveratrol significantly alleviates diabetes-induced glycation, oxidative damage, and apoptosis to inhibit DN progression |
| Palsamy and Subramanian, 2011 (50) | In vivo: Renoprotective effect of resveratrol [5 mg/(kg · d)] during diabetes | Resveratrol normalized the levels of oxidative stress, inflammatory markers, renal expression of Nrf2/Keap1, and its downstream regulatory proteins in diabetic rats | This study demonstrates resveratrol's renoprotective effect via attenuating oxidative stress markers and normalizing antioxidative Nrf2–Keap1 signaling in renal tissues of diabetic rats |
| Hussein et al., 2016 (56) | In vivo: Resveratrol [5 mg/(kg · d)] on development and progression of DN in rats | Resveratrol improved the antioxidant defense mechanism and normalized renal mRNA expressions of TGF-B1, fibronectin, NF-κB/p65, Nrf2, Sirt1, and FOXO1 | Resveratrol's anti-DN effect is mediated through improving glycemic control and attenuating oxidative damage in kidneys |
| Wang et al., 2017 (53) | In vivo: Resveratrol treatment [30 mg/(kg · d)] on hyperglycemia-induced oxidative stress in renal tubules in diabetic rats | Resveratrol ameliorated renal dysfunction and glomerulosclerosis; it also increased SIRT1 deacetylase activity, while decreasing acetylated-FOXO3a expression and oxidative stress induced by hyperglycemia | Resveratrol modulates the SIRT1/FOXO3a pathway by increasing SIRT1 deacetylase activity, and ameliorates renal tubular oxidative damage |
| Wu et al., 2012 (57) | In vivo: Protective effect of resveratrol against DN in rats | Resveratrol increased the expression of SIRT1 and FOXO1 activity; this was correlated with increased SOD activity, and decreased malondialdehyde, collagen IV, and fibronectin protein concentrations | Resveratrol-mediated modulation of SIRT1/FOXO1 pathway may be a useful therapeutic target for treatment of DN |
| Zhang et al., 2019 (55) | In vivo: Renoprotective effect of resveratrol [30 mg/(kg · d)] in diabetic mice | Resveratrol alleviated proteinuria, decreased malondialdehyde content while increasing MnSOD activity in renal cortex of diabetic mice; it also restored the expression of SIRT1 and PGC-1α | The study indicates that the renoprotective effect of resveratrol in DN is via SIRT1/PGC-1α–mediated attenuation of oxidative stress |
| Bashir, 2019 (58) | In vivo: Combined administration of resveratrol [20 mg/(kg · d)] and insulin against DN in rats | Resveratrol and insulin synergistically increased renal cortex antioxidant enzyme activities, inhibited lipid peroxidation, and upregulated Na+/K+-ATPase, independent of each other | This study suggests that combined therapy with insulin and resveratrol may be an excellent therapeutic option for DN |
| Nephroprotective effect of resveratrol via stimulating autophagy | |||
| Ma et al., 2016 (59)2 | In vitro: Resveratrol on autophagy under hypoxic conditions in renal proximal tubular cells | Resveratrol promoted SIRT1 expression, while SIRT1 knockdown attenuated the concentrations of autophagic proteins Atg7, Atg5, and LC3 and impaired the beneficial effect of resveratrol on autophagy | This study suggests SIRT1-mediated autophagy induction is a promising protective mechanism of resveratrol against DN |
| Huang et al., 2017 (60)2 | In vitro: Resveratrol on autophagy in human podocytes | Resveratrol induced autophagy and suppressed apoptosis in podocytes through regulating microRNA-383-5p (miR-383-5p); autophagy inhibition reversed the protective effects of resveratrol | Renoprotective effect of resveratrol in DN is via the activation of autophagy in podocytes, which involves miR-383-5p |
| Xu et al., 2017 (61)2 | In vitro: Effect of resveratrol (10 μmol/L) on autophagy-related genes in mouse podocytes | Resveratrol increased LC3-II/LC3-I and decreased cleaved caspase expression, likely via upregulating miRNA-18a-5p, which targeted the atactic telangiectasis mutated (ATM) gene | Regulation of autophagy via miR-18a-5p/ATM pathway is a potential therapeutic target for DN |
| Ma et al., 2016 (59) | In vivo: Resveratrol [5 mg/(kg · d)] on kidney function in diabetic rat | Resveratrol promoted SIRT1 expression and improved metabolic state of kidneys; SIRT1 knockdown in NRK-52E cells downregulated expression of autophagic proteins Atg7, Atg5, and LC3 and impaired its beneficial effect on autophagy under hypoxic conditions | The study reinforces the role of SIRT1 in resveratrol's therapeutic effect on DN via the induction of autophagy |
| Huang et al., 2017 (60) | In vivo: Resveratrol [10 mg/(kg · d)] on autophagy in db/db mice | Resveratrol regulated autophagy in db/db mice through suppressing microRNA-383-5p (miR-383-5p) expression | Activation of autophagy via miR-383-5p contributes to resveratrol's renoprotective effect in db/db mice |
| Xu et al., 2017 (61) | In vivo: Resveratrol [100 mg/(kg · d)] on autophagy in DN in db/db mice | Resveratrol increased LC3-II/LC3-I and synaptopodin expression while decreasing cleaved caspase 3; increased expression of autophagy related genes was positively correlated with miRNA-18a-5p expression | Resveratrol-mediated autophagy induction via upregulation of miR-18a-5p/ATM is a potential therapeutic option for DN |
| Nephroprotective effect of resveratrol via reducing lipotoxicity | |||
| Kim et al., 2013 (19)2 | In vitro: Resveratrol (1, 5, 50 ng/mL) on glucotoxicity in mesangial (NMS2) cells | Resveratrol prevented high-glucose–induced apoptosis in mesangial cells through inducing AMPK phosphorylation and activation of SIRT1–PGC-1α/PPARα–ERR-1α–SREBP1 | Resveratrol might protect against glucotoxicity via activation of the AMPK/SIRT1–PGC-1α signaling pathway |
| Ji et al., 2014 (62)2 | In vitro: Effect of resveratrol on AdipoR1 expression in mesangial cells (HBYZ-1) | Resveratrol treatment elevated the activity of FOXO1 and increased the expression of AdipoR1 in mesangial cells cultured in high-glucose conditions | Induction of FOXO1 activity and AdipoR1 expression may be a therapeutic target for treatment of DN |
| Park et al., 2016 (63)2 | In vitro: Resveratrol on lipotoxocity in human glomerular endothelial cells (HGECs) | Resveratrol prevented high-glucose–induced oxidative stress and apoptosis in glomerular endothelial cells by ameliorating lipotoxicity, which was evidenced by increased expression of AdipoR1 and AdipoR2 | Resveratrol protects against lipotoxicity by inhibiting oxidative stress, apoptosis, and endothelial dysfunction |
| Kim et al., 2013 (19) | In vivo: Resveratrol treatment on renal lipotoxicity and kidney function in db/db mice | Resveratrol lowered lipid concentrations, which were correlated with increased AMPK phosphorylation and activation of SIRT1–PGC-1α signaling and of the key downstream effectors, PPARα–ERR-1α–SREBP1 | Resveratrol helps prevent lipotoxicity-induced apoptosis and oxidative stress in the kidneys via activation of AMPK/SIRT1–PGC-1α signaling |
| Ji et al., 2014 (62) | In vivo: Nephroprotective effect of resveratrol in diabetic rats | Resveratrol increased AdipoR1 expression in kidneys of rats with DN, which was correlated with decreased malondialedehyde, collagen IV, and fibronectin proteins while improving kidney pathological indicators | Induction of FOXO1 activity and AdipoR1 expression is an important therapeutic target of resveratrol against DN in rats |
| Park et al., 2016 (63) | In vivo: Preventive effect of resveratrol against DN in db/db mice | Resveratrol increased phosphorylation of AMPK and SIRT1, decreased downstream effectors FOXO1 and FOXO3a via increasing AdipoR1 and AdipoR2 in renal cortex; it also increased expression of PPARγ coactivator-1α and estrogen-related receptor-1α, and decreased sterol regulatory element-binding protein 1 | The study suggests that resveratrol prevents DN by ameliorating lipotoxicity, oxidative stress, apoptosis, and endothelial dysfunction via increasing AdipoR1 and AdipoR2 expressions in kidney |
| Nephroprotective effect of resveratrol via attenuating ER stress and inflammation | |||
| Xu et al., 2014 (20) | In vitro: Resveratrol on hyperglycemia-induced mesangial cell proliferation and inflammation | Resveratrol attenuated high-glucose–induced PAI-1 expression and mesangial cell proliferation while inhibiting Akt and NF-κB activation | Anti-inflammatory effect of resveratrol in mesangial cells is likely mediated via inhibition of Akt/NF-κB pathway |
| Yuan et al., 2018 (64)2 | In vivo: Resveratrol [50 mg/(kg · d)] on DN in diabetic rats | Resveratrol decreased ER stress–associated signaling molecules p-PERK, GRP78, ATF4, and CHOP in kidneys, and these were correlated with amelioration in indicators of DN | Resveratrol is a highly safe and effective agent against DN through its modulatory action on ER response in kidney cells |
| Xu et al., 2014 (20) | In vivo: Resveratrol [10 mg/(kg · d)] on DN in diabetic mice | Resveratrol decreased the expression of PAI-1 and intercellular adhesion molecule 1 while decreasing p-Akt/Akt ratio and NF-κB in the kidneys of diabetic rats; it also significantly decreased the density of PCNA-positive cells in glomeruli | This study indicates that resveratrol helps prevent DN by inhibiting renal inflammation via Akt/NF-κB pathway |
| Nephroprotective effect of resveratrol via activating AMPK signaling pathway | |||
| Ding et al., 2010 (16)2 | In vitro: Resveratrol treatment (5, 10, 20 μmol/L) on rat renal mesangial cell proliferation | Resveratrol blocked high-glucose–induced dephosphorylation of AMPK and phosphorylation of 4E-BP1 and S6 and strongly inhibited both the DNA synthesis and proliferation of rat mesangial cells | This study suggests that resveratrol may protect against DN by inhibiting AMPK signaling pathway |
| He et al., 2016 (65)2 | In vitro: Resveratrol (20 μmol/L) on high-glucose–induced proliferation of rat kidney fibroblast cells | Resveratrol inhibited high-glucose–induced cell proliferation that was accompanied by increased p-AMPK and decreased NOX4 expression | Resveratrol is a potential therapeutic agent against fibroblast proliferation and activation via AMPK signaling pathway |
| Ding et al., 2010 (16) | In vivo: Resveratrol treatment [10 mg/(kg · d)] on renal hypertrophy in early-stage diabetes in rats | Resveratrol activated AMPK in rat kidneys and inhibited eukaryotic translation initiation factor 4E-BP1, and phospho-ribosomal protein S6 (S6), which was correlated with reduced plasma creatinine, urinary albumin excretion, and improved renal function | This study suggests that resveratrol protects against DN by activating AMPK and reducing 4E-BP1 and S6 phosphorylation |
| He et al., 2016 (65) | In vivo: Resveratrol treatment [40 mg/(kg · d)] on renal interstitial fibrosis in DN of db/db mice | Resveratrol treatment in db/db mice attenuated renal fibrosis, which was accompanied by an evident increase in p-AMPK and decrease in NOX4 | Resveratrol is a potential therapeutic agent against diabetic renal fibrosis via regulation of AMPK/NOX4/ROS signaling |
| Nephroprotective effect of resveratrol via modulating angiogenesis | |||
| Wen et al., 2013 (66)2 | In vitro: Antiangiogenic activity of resveratrol in mouse podocytes and endothelial cells | Resveratrol downregulated high-glucose–induced VEGF and Flk-1 expression in cultured mouse glomerular podocytes and endothelial cells | Resveratrol has the potential to suppress angiogenesis by downregulating VEGF/Flk-1 signaling |
| Wen et al., 2013 (66) | In vivo: Antiangiogenic activity of resveratrol [20 mg/(kg · d)] against DN in rats | Resveratrol decreased expression of VEGF, Flk-1, and angiopoietin 2, and increased expression of Tie-2 in rat kidneys, which was accompanied by improved kidney function | This study reinforces an important role of resveratrol's antiangiogenic activity in its beneficial effect on DN |
1AdipoR1, adiponectin receptor 1; AdipoR2, adiponectin receptor 2; AGE, advanced glycation end-product; Akt, protein kinase B; AMPK, AMP kinase; ATF, activating transcription factor; ATG, autophagy related; CHOP, C/EBP homologous protein; DN, diabetic nephropathy; EMT, epithelial to mesenchymal transition; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ERR-1α, estrogen-related receptor 1α; Flk-1, fetal liver kinase; FOXO, forkhead box O; GRP78, glucose-regulated protein 78; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; LC3, microtubule-associated protein 1A/1B-light chain 3; MnSOD, manganese superoxide dismutase; NOX1, NAD(P)H oxidase 1; NOX4, NAD(P)H oxidase 4; NRF1, nuclear respiratory factor 1; NRF2, nuclear factor erythroid 2–related factor 2; p-, phosphorylated; PAI-1, plasminogen activator inhibitor 1; PCNA, proliferating cell nuclear antigen; protein kinase R-like ER kinase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; PPARα, peroxisome proliferator-activated receptor α; PPARγ, peroxisome proliferator-activated receptor γ; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, superoxide dismutase; SREBP1, sterol regulatory element-binding transcription factor 1; TGF-B1, transforming growth factor B1; VEGF, vascular endothelial growth factor; 4E-BP1, 4E binding protein 1.
2
In vitro studies were conducted using human-derived cell lines.