Renoprotective Effects of Mangiferin: Pharmacological Advances and Future Perspectives

Abstract

Both acute and chronic kidney diseases substantially contribute to the morbidities and mortality of patients worldwide. The existing therapeutics, which are mostly developed from synthetic sources, present some unexpected effects in patients, provoking researchers to explore potential novel alternatives. Natural products that have protective effects against various renal pathologies could be potential drug candidates for kidney diseases. Mangiferin is a natural polyphenol predominantly isolated from Mangifera indica and possesses multiple health benefits against various human ailments, including kidney disease. The main objective of this review is to update the renoprotective potentials of mangiferin with underlying molecular pharmacology and to highlight the recent development of mangiferin-based therapeutics toward kidney problems. Literature published over the past decade suggests that treatment with mangiferin attenuates renal inflammation and oxidative stress, improves interstitial fibrosis and renal dysfunction, and ameliorates structural alteration in the kidney. Therefore, mangiferin could be used as a multi-target therapeutic candidate to treat renal diseases. Although mangiferin-loaded nanoparticles have shown therapeutic promise against various human diseases, there is limited information on the targeted delivery of mangiferin in the kidney. Further research is required to gain insight into the molecular pharmacology of mangiferin targeting kidney diseases and translate the preclinical results into clinical use.

Keywords: chronic kidney disease; inflammation; kidney fibrosis; mangiferin; oxidative stress; renoprotective.

Figure 1

Structure of mangiferin (PubChem CID 5281647).

Figure 2

Mechanisms involved in the pathogenesis of oxidative stress in the kidney. NADPH oxidase is the main source of cellular ROS. Nox4 is an isoform of NADPH oxidase expressed in renal tubules that leads to oxidative stress (ROS and MDA) and damages the kidney. Stress stimuli, for instances cisplatin, STZ, ischemia result in decreased Nrf2 thus leading to oxidative stress. Reactive oxygen species, ROS; MDA, malondialdehyde; streptozotocin, STZ; NF-E2-related factor 2, Nrf2.

Figure 3

Mechanisms involved in the pathogenesis of inflammation in the kidney. Stress stimuli example for, cisplatin, DGal, STZ, LPS, OPN, high glucose, and H₂O₂ generate ROS in the kidney. Accumulation of ROS induces inflammation through the activation of the NLRP3 inflammasome. NLRP3 involves a multi-protein complex known as inflammasome, which triggers the NF-κB signaling pathway. HMGB1 protein is a late inflammation instigating compound which activates the NF-κB signaling pathway by binding with Toll-like receptors. The NF-κB pathway further promotes an inflammatory storm by releasing inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18), which ultimately leads to kidney damage. High-mobility group box 1; HMGB1, D (+) galactosamine; DGal, osteopontin; OPN, Streptozotocin; STZ, reactive oxygen species; ROS, IL-6; interleukin-6, IL-1β; Interleukin 1β, TNFα; Tumor Necrosis Factor-α.

Figure 4

This schematic representation shows that stress stimuli example for, cisplatin, DN, Ischemia, and sepsis mediates various pathological conditions including cytotoxicity, oxidative stress, inflammation, fibrosis, autophagy dysfunction, and mitochondrial dysfunction. These ultimately lead to kidney damage. Stress stimuli activate the NF-kB signaling pathway which triggers the release of inflammatory cytokines (TNF-α, IL-6, IL-18, IL-8, and IL-1β) and decreases the action of ULK-1 thus autophagy impairment causes. Further col-1, FN, α-SMA causes accumulation of extracellular matrix (ECM) resulting in fibrosis. Mangiferin protects the kidney by suppressing the cascades of inflammatory pathways, oxidative stress, fibrosis, cytotoxicity, mitochondrial dysfunction, and autophagy impairment. ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; FN, fibronectin; α-SMA, α-smooth muscle actin; Col I, collagen I; TGF-β1, transforming growth factor, ULK-51, unc-51-like kinase; DN, diabetic nephropathy; HN, hyperuricemic nephropathy; NF-kB, nuclear factor-kappa B.