Gallic acid ameliorates calcium oxalate crystal-induced renal injury via upregulation of Nrf2/HO-1 in the mouse model of stone formation

Donghui Zhou; Yan Wu; Heng Yan; Tianyu Shen; Si Li; Junbo Gong; Gang Li; Haixing Mai; Dekun Wang; Xiaoyue Tan

doi:10.1016/j.phymed.2022.154429

Gallic acid ameliorates calcium oxalate crystal-induced renal injury via upregulation of Nrf2/HO-1 in the mouse model of stone formation

Phytomedicine. 2022 Nov:106:154429. doi: 10.1016/j.phymed.2022.154429. Epub 2022 Sep 5.

Authors

Donghui Zhou¹, Yan Wu¹, Heng Yan¹, Tianyu Shen¹, Si Li², Junbo Gong², Gang Li³, Haixing Mai⁴, Dekun Wang⁵, Xiaoyue Tan⁶

Affiliations

¹ School of Medicine, Nankai University, Tianjin 300071, China.
² School of Chemical Engineering and technology, Tianjin University, Tianjin, China.
³ Nephrology Division, The Second Hospital of Tianjin Medical University, Tianjin, China.
⁴ Department of Urology, the Third Medical Centre, Chinese PLA General Hospital, Beijing, China.
⁵ School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: wangdekun@nankai.edu.cn.
⁶ School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: xiaoyuetan@nankai.edu.cn.

PMID: 36099652
DOI: 10.1016/j.phymed.2022.154429

Abstract

Background: High prevalence and reoccurrence rate of nephrolithiasis bring about serious socioeconomic and healthcare burden, necessitating the need of effective therapeutic agents. Previous study revealed that gallic acid (GAL) alters the nucleation pathway of calcium oxalate (CaOx). On the other hand, it appears protective role against oxidative injury. Whether GAL could protect against crystal-induced lesion in vivo, and its underlying mechanism is yet unsolved.

Purpose: This study aims to investigate the protective effects of GAL on the crystal-induced renal injury and its underlying mechanism in the mouse model of stone formation induced by glyoxylic acid.

Study design and methods: The mouse model of stone formation was established via successive intraperitoneal injection of glyoxylate. Proximal tubular epithelial cell line HK-2 treated with calcium oxalate monohydrate (COM) was used as in vitro model. The protective role of GAL on nephrolithiasis was tested by determination of tubular injury, crystal deposition and adhesion, levels of inflammatory cytokines, macrophage infiltration and the redox status of kidney. In vitro, effect of GAL on the ROS level and oxidative tubular injury induced by COM were detected, as well as major antioxidant pathway Nrf2/HO-1.

Results: Administration of GAL alleviates the renal deposition and adhesion of CaOx stone. Meanwhile, GAL ameliorates the inflammation and renal tubular injury. Level of intracellular ROS, osteopontin and CD44 are reduced, either in the mouse model of stone formation or in the COM-treated HK-2 cells after treatment of GAL. Mechanistically, GAL activates Nrf2/HO-1 pathway in HK-2 cells. Silencing Nrf2 abrogates the protective effect of GAL on the oxidative injury and adhesion of COM in HK-2 cells.

Conclusion: Taken together, our study demonstrates the protective effect of GAL on the deposition of kidney stone and consequent tubular injury. Induction of the antioxidant pathway Nrf2/HO-1 was found to decrease the level of ROS and oxidative injury, thus implying that GAL could be a potential therapeutic agent for the treatment of nephrolithiasis.

Keywords: Gallic acid; Nephrolithiasis; Nrf2; Oxidative stress.

MeSH terms

Animals
Antioxidants / metabolism
Calcium Oxalate* / metabolism
Disease Models, Animal
Gallic Acid / pharmacology
Glyoxylates
Kidney
Mice
NF-E2-Related Factor 2 / metabolism
Nephrolithiasis* / chemically induced
Nephrolithiasis* / drug therapy
Osteopontin / metabolism
Oxidative Stress
Reactive Oxygen Species / metabolism
Up-Regulation

Substances

Antioxidants
Calcium Oxalate
Gallic Acid
Glyoxylates
NF-E2-Related Factor 2
Osteopontin
Reactive Oxygen Species