Therapeutic potential of mangiferin against kidney disorders and its mechanism of action: A review

Abstract

There is a swing in research developments concerning the utilization of natural products as effective pharmacotherapeutic agents due to their comparatively lower toxicities than synthetic compounds. Among natural products, mangiferin is a natural C-glucosyl xanthonoid polyphenol with remarkable pharmacological activities. Emerging evidence indicates the therapeutic benefits of mangiferin against various kidney disorders, including renal injury, diabetic nephropathy, renal fibrosis, hyperuricemic nephropathy, and lupus nephritis, in experimental animal models. The mangiferin induced antioxidant response resulting in vital functions, such as protection against renal inflammation, inhibits renal cell apoptosis, activates autophagy, causes immunomodulation, regulates renal urate transporters and modulates cell signalling pathways. The purpose of this review provide a brief overview of the in vitro/in vivo reno-protective effect of mangiferin and the underlying mechanism(s) in protecting against kidney disorders. Understanding the pharmacological actions of mangiferin is prominence due to its excellent therapeutic potential in managing kidney disorders. Thus, in addition to this review, in-silico molecular docking is performed against nuclear factor kappa B (NF-κB) and soluble epoxide hydrolase (sEH) to study the mechanism of action of mangiferin. It is believed that mangiferin is a safe reno-protective molecule. The observed positive effects are attributed to the inhibition of inflammation caused by NF-κB and sEH upregulation and oxidative stress activation. Studies on the efficacy and safety of mangiferin in clinical trials are further warranted to confirm its medicinal potential as therapeutic agent for kidney disorders in humans.

Keywords: Drug delivery; In-silico; Kidney disorders; Mangifera indica; Mangiferin; Reno-protective.

Fig. 1

Structure of mangiferin.

Fig. 2

Anatomy of the kidney. The renal cortex and renal medulla are visible in the frontal sections of the kidney. Renal columns made of connective tissue separate 5–8 renal pyramids in the medulla. Each pyramid produces urine and eventually leads to a renal papilla. Each renal papilla drains into a minor calyx, which unites to form a major calyx. All major calyces connect to the one renal pelvis, which links to the ureter. The figure was created with the support of BioRender.com under a paid subscription.

Fig. 3

Effect of mangiferin in diabetic nephropathy. The pathophysiology of diabetic nephropathy is multifaceted, involving metabolic and hemodynamic alterations, chronic inflammation, activation of the renin-angiotensin system, and oxidative stress. The activation of AGEs, autoxidation of glucose, and xanthine oxidase activity are some of the most likely main sources of ROS production. PKC isoforms, TGF-β1 pathways, and NF-kB were found to be implicated in diabetic nephropathy's oxidative stress-mediated signaling cascades. In the hyperglycemic state, TNF-α was produced, which activated caspase 8, cleaved Bid to tBid, and finally activated the mitochondria-dependent apoptotic pathway. Following hyperglycemia, mangiferin therapy successfully suppressed all of these alterations and preserved the cells from apoptosis. Several novel markers for early disease detection have emerged from the pathologic processes of underlying renal dysfunction and damage. In normoalbuminuric patients with diabetes mellitus type 1, poor glycemic control is an independent predictor of progression to proteinuria (albuminuria). Abbreviations: AGEs, Advanced glycation end products; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; Bid, BH3-interacting domain death agonist; Cyto C, Cytochrome; cMAPKs, mitogen-activated protein kinases; MMP, Mitochondrial membrane potential; NF-κB, Nuclear factor kappa light chain enhancer of activated B cells; PKC, Protein kinase C; ROS, Reactive oxygen species; tBid, Truncated form of Bid; TGF-1β, Transforming growth factor beta 1; TNF-α, T necrosis factor α.

Fig. 4

Protective effect of mangiferin against kidney-inflammation and HN. XO is a fundamental pharmacological target in anti-hyperuricemic treatment since it is the major enzyme in catalyzing uric acid synthesis. The C-glucosyl linkage and polyhydroxy groups in mangiferin's structure contribute mostly to its free radical-scavenging activity, allowing it to suppress the generation of ROS as a consequence, resulting in a reduction in oxidative stress. Thirdly, its ability to modulate the expression of different proinflammatory signaling intermediates like TNF-α, as well as inhibiting the pathogenesis and inflammation of the kidney by modulating JNK, TGF-β1, NF-B, CD73, Nrf2, NLRP3, and their downstream signaling molecules, contribute to its protective mechanism. Mangiferin effectively lowers uric acid levels via enhancing AQP2-related uric acid excretion and decreasing XO-mediated uric acid synthesis. By acting as an antioxidant, anti-fibrotic and anti-inflammatory agent decreased uric acid or resulted in reducing the risk of HN. Abbreviations: AMPK, AMP-activated protein kinase; AQP2, Aquaporin 2; HN, Hyperuricemic nephropathy; IL-1β, Interleukin-1β; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-18, Interleukin-18; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases; NF-κB, Nuclear factor kappa light chain enhancer of activated B cells; NLRP3, Nod-like receptor protein 3; Nrf2, Nuclear factor erythroid 2-related factor 2; PKC, Protein kinase C; TGF-1β, Transforming growth factor beta 1; TNF-α, T necrosis factor α; XO, Xanthine oxidase.

Fig. 5

Stereo-view of mangiferin docked into the DNA binding region of (A) NF-κB (1NFK) and (B) active site of sEH (3ANS). The best docked postions of protein–ligand interaction of mangiferin with (C) NF-κB and (D) sEH.

Fig. 6

Possible drug delivery system of mangiferin for kidney disorders. Kidney-targeted drug delivery systems (KDDSs) serve as an interesting approach and favorable options for optimizing the pharmacokinetic profile of mangiferin and minimizing the undesired side effects. Following oral delivery, mangiferin was subjected to the first-pass effect, which is a significant barrier for mangiferin. Therefore, Liposomal encapsulation, polymeric nanoparticles, and emulsions are being used to regulate the distribution of phytochemicals and to address some of the shortcomings related to free compounds, such as poor bioavailability. The glomerular vascular fenestrations, which normally have a width of 70–130 nm, provide direct access to the mesangial region thus nanocarriers with dimensions of 70–130 nm, can thereby extravasate via the glomerular vasculature for in-situ targeting in the mesangial region.

Fig. 7

Overview of reno-protective actions of mangiferin against kidney disorders through different signaling pathways. Mangiferin significantly reduced kidney morphological damage as well as inflammation, fibrosis, and apoptotic histological markers. The inflammatory cytokines IL-1, IL-6, IL-8, IL-18, and TNF- α were also decreased by mangiferin. The anti-inflammatory and antioxidant actions of mangiferin were mediated by Nrf2 and NF-κB. Abbreviations: AGEs, Advanced glycation end products; AMPK, AMP-activated protein kinase; AQP2, Aquaporin 2; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; Glo-1, glyoxalase; IL-1β, Interleukin-1β; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-18, Interleukin-18; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; MAPKs, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; OAT10, renal organic anion transporter 10; NF-κB, Nuclear factor kappa light chain enhancer of activated B cells; NLRP3, Nod-like receptor protein 3; Nrf2, Nuclear factor erythroid 2-related factor 2; PKC, Protein kinase C; ULK1, Unc51-like kinase 1; rGLUT9, renal glucose transporter 9; rURAT1, renal urate-anion transporter 1; TGF-1β, Transforming growth factor beta 1; TNF-α, T necrosis factor α; Tregs, Regulatory T cells.