Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice.

Jung-Yeon Kim,Jaechan Leem,Eon Ju Jeon

doi:10.3390/biom10010011

Jung-Yeon Kim, Jaechan Leem + Show 1 more

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https://doi.org/10.3390/biom10010011

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Journal: Biomolecules	Publication Date: Dec 19, 2019
Citations: 37	License type: CC BY 4.0

Affiliation: Catholic University of Daegu

Abstract

Melatonin, a pineal hormone, is well known to regulate the sleep–wake cycle. Besides, the hormone has been shown to display pleiotropic effects arising from its powerful anti-oxidant and anti-inflammatory activities. Recent studies have reported that melatonin exerts protective effects in animal models of kidney disease. However, the potential effects of melatonin on aristolochic acid (AA)-induced nephropathy (AAN) have not yet been investigated. Here, we found that the administration of melatonin ameliorated AA-induced renal dysfunction, as evidenced by decreased plasma levels of blood urea nitrogen and creatinine and histopathological abnormalities such as tubular dilatation and cast formation. The upregulation of tubular injury markers after AA injection was reversed by melatonin. Melatonin also suppressed AA-induced oxidative stress, as evidenced by the downregulation of 4-hydroxynonenal and reduced level of malondialdehyde, and modulated expression of pro-oxidant and antioxidant enzymes. In addition, p53-dependent apoptosis of tubular epithelial cells, infiltration of macrophages and CD4+ T cells into damaged kidneys, and renal expression of cytokines and chemokines were inhibited by melatonin. Moreover, melatonin attenuated AA-induced tubulointerstitial fibrosis through suppression of the tumor growth factor-β/Smad signaling pathway. These results suggest that melatonin might be a potential therapeutic agent for AAN.

Highlights

Aristolochic acid (AA) is a toxic compound found in medicinal plants, including genus Aristolochia and Asarum, and has been used in traditional Chinese medicine [1]
As expected,It histological analyses that AA-treated mice and exhibited structuralinalterations such has been shown that AArevealed induces structural abnormalities renal dysfunction rodents as tubular and cast formation compared to vehicle-treated mice
We showed that administration of melatonin effectively ameliorates acute renal failure, as evidenced by a reduction in plasma levels of blood urea nitrogen (BUN) and creatinine and histopathological alterations such as tubular dilatation, cast formation, and interstitial fibrosis induced by AA

Summary

Introduction

Aristolochic acid (AA) is a toxic compound found in medicinal plants, including genus Aristolochia and Asarum, and has been used in traditional Chinese medicine [1]. The AA-induced nephropathy (AAN) was first identified in the 1990s in Belgium. New cases of AAN have been regularly reported in other countries and its true incidence is largely unknown and probably underestimated [2]. The disease is clinically characterized by rapidly progressive fibrosing interstitial nephritis that can often cause end-stage renal disease. There is currently no specific therapy for treating AA-induced renal injury. Many efforts have been made over the last two decades to elucidate the pathophysiology of AAN because an understanding of its mechanisms can shed light on the development of new therapeutic approaches. Accumulating evidence suggests that oxidative stress, tubular cell apoptosis, inflammation, and fibrosis are important pathogenic processes for the disease, its detailed molecular mechanisms remain unclear [1,2]

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