Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials

Figures & data

Table 1. Oxidative stress and postulated pathways involved in diabetic nephropathy.

Reactive nitrogen species	Reactive oxygen species	Reactive oxygen species scavenging enzymes	Postulated pathways involved in diabetic nephropathy
Nitric oxide Nitrogen dioxide Peroxynitrite Nitrous oxide Alkyl peroxynitrites              Interact with thiol groups Unsaturated fatty acid	Hydroxyl radical Singlet oxygen Hydrogen peroxide Hypochlorite radical Superoxide anion Peroxyl radicals Hydroperoxyl radicals              Oxidative damage Increased cytokines Sources of reactive oxygen species Cyclo-oxygenase Cytochrome P450 Mitochondrial electron transport chain NADPH oxidase	Superoxide dismutase Catalase All trans retinol 2 B-carotene Ascorbic acid Alpha-tocopherol Thiol antioxidants system: Peroxiredoxin Thioredoxin Glutathione/Glutaredoxin Glutathione peroxidase Glutathione transferase	Hyperglycemia Oxidative stress Advance glycation end products Renin–angiotensin–aldosterone system Aldol reductase Polyol pathway Protein kinase C Insulin growth factor-1 Transforming growth factor-β

Figure 1. Role of high blood sugar and transcriptase factors in OS in DM and DN and the effects of natural products. ⊕: activate or stimulate; ⊗: deactivate or inhibit; GSTs: glutathione-s-transferase; OS: oxidative stress; NO: nitric oxide; TNF-α: tumor necrosis factor; GCS: γ-glutamyl-cysteine synthetase; ROS: reactive oxygen species; PCK: protein kinase C; SOD: superoxide dismutase; RNS: reactive nitrogen species; AGEs: advanced glycation end products; NFκB: nuclear factor kappa B; NrF2: nuclear factor erythroid 2-related factor 2; HO1: heme oxygenase-1; NQO1: NAD(P)H quinone oxidoreductase 1; MCP-1: monocyte chemoattractant protein-1; IKK-β: inhibitor of nuclear factor kappa-B kinase subunit beta; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha.

Table 2. Effects of common plants and spices on kidney function in diabetic animals and human experiments with suggested mechanism of action.

Name of the plants/herbs (active ingredients)	Effects on diabetic nephropathy in rate or mice	Mechanism of action	References
Ginger (Gingerdione) (Zerumbone) (Gingerol)	Decreases BGL, increases insulin release Decreases BUN, urinary albumin Reduces antioxidants SOD and CAT and lowers MDA level Attenuates the progression of structural nephropathy Increase GSH level and GSH/GSSG ratio	Antioxidant Anti-inflammatory Increases NQO1 activity Decreases iNOS, MCP-1, TGF-β1, and NFκB activation Upregulates the expression of ARE-target genes Reducing degradation of IκBα	[49–64]
Turmeric (Curcumin) (Curcuminoids)	Induces expression of SOD, CAT, GR, GPx, HO-1, and GST Lowers mesangial area, proteinuria, BUN, and SCr Protects the kidneys of rats or mice with DM Inhibits inflammatory gene expression and ameliorates DN Prevents epithelial–mesenchymal transition of podocytes and proteinuria Decreases albuminuria and attenuates glomerular sclerosis Lowers mesangial area, proteinuria, BUN, and SCr	Antioxidant Anti-inflammatory Induction of Nrf2 Suppresses phosphorylation of caveolin-1 Inhibits phosphorylation of STAT3 and degradation of IκB	[65–82]
Coenzyme Q10	Attenuates diabetes-induced decreases in antioxidant defense mechanisms Inhibits leukocyte infiltration, glomerulosclerosis, and MDA Increases serum levels of GSH, CAT, and SOD Prevents altered mitochondrial function and morphology, glomerular hyperfiltration, and proteinuria	Antioxidants Induces Nrf2 nuclear translocation Suppresses TGF-β1	[83–90]
Green tea (Catechins) (Epigallocatechin-3-gallate)	Protects kidney against gentamycin, cyclosporine, and i.v. contrast Has renoprotective properties comparable with ACEi Reduced BGL, HBA1c, SCr, and BUN Attenuates proteinuria, hyperfiltration, glomerulosclerosis, and tubulointerstitial fibrosis Ameliorates cisplatin-induced acute kidney injury and lupus nephritis	Antioxidant Anti-inflammatory Increases Nrf2 and NQO1 mRNA Diminishes AKT/ERK/NFκB pathways Activates Sirt1	[91–105]
Guava (Psidium guajava) (Total triterpenoids)	Decreases BGL and increases the insulin sensitivity index Protects renal lesions in diabetic rats Decreases BUN and SCr and improves the renal structural damages	Antioxidant Anti-inflammatory Inhibition of NFκB activation Suppresses LPS-induced IκB-α degradation Inhibits iNOS, COX-2	[106–110]
Grape seed (Resveratrol) (Pterostilbene) (Proanthocyanindin)	Increases renal antioxidant enzyme activity and ameliorates DN Decreases proteinuria, suppresses AGEs/RAGE axis Improves renal function parameters Decreases proteinuria, attenuates the progression of nephropathy in diabetic rats 5-reduced albuminuria Decreases fasting BGL, serum insulin, HbA1c, and systolic blood pressure	Antioxidant, anti-inflammatory Reduces the levels of CRP and the expression of TNF-α, monocyte chemoattractant protein 1, and intercellular adhesion molecule 1 Inhibiting NFκB activation and subsequent iNOS and COX-2 expression Increases ARE-responsive HO-1 and GSR Down regulating expression of CTGF Suppresses AGEs/RAGE	[178–188]
Ginkgo biloba	Reduces OS, and improves the renal tissue structure and renal functions Protects against glomerulosclerosis of mesangial cells Decreases BGL, Scr, BUN, urine protein, and OS Inhibits AGEs production Improves renal tissue structure and renal functions Decreases the urinary albumin excretion, BGL, SCr, and BUN in diabetic patients	Antioxidants and anti-inflammatory Inhibits sAGEs production Reduces CTGF and TGF-β1 mRNA Increases Nrf2 and upregulation of HO-1	[189–197]
Flaxseed (omega-3 fatty acid)	Prevents heavy metals-induced nephrotoxicity and OS damage Reduces proteinuria and glomerular and tubulointerstitial lesions Reduces levels of OS and increases the antioxidant defense systems Protects rodents against ischemic acute renal failure, IgA- or cyclosporine A-induced nephrotoxicity, and STZ-induced type 1 and type 2 DN Attenuates tubulointerstitial fibrosis and inflammation	Antioxidants and anti-inflammatory Inhibits thromboxan A2 and B, prostaglandin E, and prostaglandin I, activating protein-1, MCP-1, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling	[198–212]
Astragalus membranaceus (Calycosin) (Calycosin-7-O-beta) (d-glucoside)	Has renal protective effect in DN patients Reduces BUN, SCr, BGL, and albuminuria in diabetic patients Reverses the glomerular hyperfiltration state Ameliorates the pathological changes of early DN	Has anti-inflammatory and antioxidant activity Upregulates c-met (a receptor tyrosine kinase) expression in human kidney Reduces TGF-β1 expression Reduces mRNA level of NFκB Increases in inhibitory NFκB protein mRNA expression Modulates TGF-β/Smad signaling	[223–233]
Cinnamon (Polyphenol) (Cinnamaldehyde)	Reduces BSL Has in vitro and in vivo insulin-enhancing biological activity Has protection against alloxan-induced renal damage Reduces urinary albumin and creatinine	Antioxidant and antidiabetic activity Inhibits AGE Induces Nrf2 transcriptional activity Upregulates cellular protein levels of Nrf2, GSH levels, and HO-1 and gamma-glutamyl-cysteine synthetase Upregulates cellular GHS levels Regulates Nrf2 Increases ARE-luciferase activity Upregulates thioredoxin reductase-1	[213–222]
Rosa laevigata Michx	Ameliorates renal dysfunction cell injury Decreases SCr and BUN levels	Antioxidant Anti-inflammatory Inhibits expression of NFκB p65 and MCP-1 increases in the expression of the IκBα protein Upregulates the levels of Nrf2, Sirt1 and HO-1 Downregulates the levels of KEAP1 and NFκB p65	[111–113]
Garlic (Allicin) (S-allylcysteine) (Diallyl trisulfide)	Reduces hyperglycemia Attenuates mesangial expansion and glomerulosclerosis Decreases urinary excretions of albumin Decreases BGL, BUN, and SCr Normalizes blood pressure and renal clearance function	Antioxidant Anti-inflammatory Reduces RAGE Activates the Nrf2–ARE signaling pathway Decreases the expression of VEGF Decreases levels of collagen I, TGF-β1 and p-ERK1/2	[114–130]
Black seed (Thymoquinone)	Reduces the elevated levels of BGL in diabetic rats Stimulates insulin release Lowers SCr and BUN Improves renal function Reduces renal inflammation and oxidative injury in ischemia reperfusion injury Ameliorates albuminuria	Antioxidant Anti-inflammatory Reduces TNF-α Inhibits the phosphorylation of mitogen-activated protein kinases production of NO by iNOS enzyme Suppresses NFκB activation Restores the decrease in IL-10 levels and Nrf2 mRNA levels	[131–146]
Panax ginseng (Ginsenosides) (Panaxytriol)	Reduces the cisplatin-induced nephrotoxicity Ameliorates hyperglycemia and renal damage in diabetic rats Decreases hyperglycemia and proteinuria Augments creatinine clearance	Antioxidant ARE inducer Induces NQO1 Upregulates aldo–keto reductases enzymes	[147–154]
Fenugreek (Fenugreek oil) (GII) (Glycosides)	Ameliorates SCr in diabetic animals Reduces the high levels of BGL, BUN, SCr, and IL-6 Reduces BGL, improves renal functions Suppresses ECM accumulation Attenuates the cisplatin-induced biochemical and histopathological alterations, inflammation, and apoptosis kidney	Antioxidant Anti-inflammatory Restrains TGF-β1/CTGF signaling pathway Induces Nrf2 Increases the concentration of GSH and the activity of both SOD and CAT	[155–162]
Rosmarinus officinalis (Rosmarinic acid) (Carnosic acid)	Decreases focal glomerular necrosis, dilatation of Bowman’s capsule, degeneration of tubular epithelium, necrosis in tubular epithelium, and tubular dilatation Prevents ischemia/reperfusion injury in the kidneys Ameliorates glomerulosclerosis	Antioxidant and anti-inflammatory Inhibits CTGF Reduces NFκB Increases glutathione transferase, anti Bcl-2 activity, and scavenger of peroxynitrite Activates Nrf2	[163–177]
Vitamin C	Protects podocyte by increasing antioxidative capacity and ameliorating the renal OS Reduces albuminuria, and GBM thickness in the kidneys Decreases BUN, SCr, and urinary albumin excretion rate Increases creatinine clearance rate Lowers albuminuria in type 2 diabetic patients with microalbuminuria Reduces HbA1c levels in diabetic patients	Antioxidants and anti-inflammatory Increases HO-1 protein expression in a concentration- and time-dependent manner Causes Nrf2 activation Downregulates expressions of collagen type IV	[234–243]
Vitamin E (Tocotrienol)	Ameliorates SCr in diabetic animals Normalizes elevated baseline creatinine clearance in type 1 diabetic patients Reduces HbA1C levels in type 2 diabetes Decreases microalbuminuria Has a nephroprotective effect Reduces proximal tubular injury and renal LPO	Suppresses the activation of NFκB signaling pathway Antioxidant Decreases thromboxane A2 production Increases GSH level and CAT activity Improves the index of NO^2–/NO^3– generation	[244–251]
Zinc	Has a favorable effect on glycemic control in diabetic patients Reduces diabetes-induced renal damage Decreases BSL, triglyceride, urinary albumin excretion, and inflammation in type 2 diabetic nephropathy patients	Antioxidant properties and anti-inflammatory Prevents hyperglycemia-induced CTGF expression Causes stimulation of metallothionein synthesis Upregulates Nrf2 function via activating Akt-mediated inhibition of Fyn function	[252–259]
Oats (Oat β-d-glucan) (Avenanthramides)	Slow down renal fibrosis Reduce BGL, HbA1c, and OS markers Lower BSL and HbA1c in diabetic patients	Downregulates the TGF-β1 and receptors for AGE expression at mRNA levels Causes disruption of the detrimental receptors for AGE-NFκB axis Normalizes NFκB activation and TNF-α expression Increases HO-1 expression which was mediated by Nrf2 translocation	[260–264]
Lycopus lucidus Turcz	Inhibits renal fibrosis Has a protective effect on renal damage of STZ-induced DN in rats Ameliorates expansion of the mesangial area Decreases SCr and BUN	Blocks TGF-β signaling pathway Suppresses the translocation and promoter transcriptional activity of NFκB Improves OS and regulates p-Akt and CTGF Suppresses rhTGF-β1-induced Smad2 and ERK1/2 activation Downregulates the expression of TGF-βRI, TGF-βRII, Smad4, and Smad7	[265–268]
Milk thistle (Flavonolignans) (Silymarin)	Reduces urinary excretion of albumin Has a protective effect against high glucose-induced podocyte injury Lowers levels of BSL, HbA1c, urine volume, SCr, serum uric acid, and urine albumin Decreases levels of HbA1c Increases SOD, GPx activity, and total antioxidant capacity Reduces CRP levels, and decreases MDA concentration in diabetic patients Decreases the urinary albumin–creatinine ratio, urinary levels of TNF-α, and urinary and serum levels of MDA in diabetic patients	Antioxidant and anti-inflammatory effects Reverses STZ-induced downregulation of Sirt-1 expression Decreases the NADPH oxidase, iNOS and NFκB over expression and upregulates the Nrf2 expression	[269–274]

GSTs: Glutathione-s-transferase; OS: oxidative stress; NO: nitric oxide; TNF-α: tumor necrosis factor; GCS: γ-glutamyl-cysteine synthetase; ROS: reactive oxygen species; PCK: protein kinase C; SOD: superoxide dismutase; RNS: reactive nitrogen species; AGEs: advanced glycation end products; NFκB: nuclear factor kappa B; NrF2: nuclear factor erythroid 2-related factor 2; HO1: heme oxygenase-1; NQO1: NAD(P)H quinone oxidoreductase 1; MCP-1: monocyte chemoattractant protein-1; IKK-β: inhibitor of nuclear factor kappa-B kinase subunit beta; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha.