Gegen Qinlian Decoction Ameliorates Hyperuricemia-Induced Renal Tubular Injury via Blocking the Inflammatory Signaling Pathway

Xiao-Jun Wang; Yi-Ding Qi; Hao-Chen Guan; Hua-Gang Lin; Pei-Qing He; Kang-Wei Guan; Lei Fu; Mao-Qing Ye; Jing Xiao; Tao Wu

doi:10.3389/fphar.2021.665398

Gegen Qinlian Decoction Ameliorates Hyperuricemia-Induced Renal Tubular Injury via Blocking the Inflammatory Signaling Pathway

Front Pharmacol. 2021 May 4:12:665398. doi: 10.3389/fphar.2021.665398. eCollection 2021.

Authors

Xiao-Jun Wang^{1

2}, Yi-Ding Qi³, Hao-Chen Guan⁴, Hua-Gang Lin⁵, Pei-Qing He¹, Kang-Wei Guan¹, Lei Fu², Mao-Qing Ye^{2

3}, Jing Xiao^{2

5}, Tao Wu^{1

2}

Affiliations

¹ Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
³ Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
⁴ Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, China.

Abstract

Background: Gegen Qinlian decoction (GGQLD) is a typical traditional Chinese medicine (TCM) prescription documented in Shang Han Lun. Clinically, GGQLD has been utilized to manage the inflammatory symptoms of metabolic diseases and to protect against renal damage in China. In the present study, a hypothesis was proposed that the multi-target solution of GGQLD produced anti-inflammatory effects on ameliorating hyperuricemia (HUA). Methods: A total of 30 primary HUA patients receiving GGQLD treatment (two doses daily) for 4 weeks were selected. Then, differences in uric acid (UA) levels and expression of peripheral blood mononuclear cells (PBMCs) and urinary exosomes before and after treatment were analyzed. The therapeutic indexes for the active ingredients in GGQLD against HUA were confirmed through pharmacological subnetwork analysis. Besides, the HUA rat model was established through oral gavage of potassium oxonate and treated with oral GGQLD. In addition, proximal tubular epithelial cells (PTECs) were stimulated by UA and intervened with GGQLD for 48 h. Subsequently, RNA-seq, flow cytometry, and confocal immunofluorescence microscopy were further conducted to characterize the differences in UA-mediated inflammation and apoptosis of human renal tubular epithelial cells pre- and post-administration of GGQLD. In the meanwhile, quantitative real-time PCR (qPCR) was carried out to determine gene expression, whereas a western blotting (WB) assay was conducted to measure protein expression. Results: Our network analysis revealed that GGQLD treated HUA via the anti-inflammatory and antiapoptotic pathways. Additionally, NLPR3 expression significantly decreased in PBMCs and urinary exosomes of HUA patients after GGQLD treatment. In vivo, GGQLD treatment alleviated HUA-induced renal inflammation, which was associated with decreased expression of NLRP3 inflammasomes and apoptosis-related mRNAs. Moreover, GGQLD promoted renal UA excretion by inhibiting the activation of GSDMD-dependent pyroptosis induced by NLRP3 inflammasomes and by reducing apoptosis via the mitochondrial apoptosis signaling pathway in vitro. Conclusion: This study indicates that GGQLD efficiently reduces inflammatory responses while promoting UA excretion in HUA. Our findings also provide compelling evidence supporting the idea that GGQLD protects against the UA-mediated renal tubular epithelial cell inflammation through the mitochondrial apoptosis signaling pathways. Taken together, these findings have demonstrated a novel therapeutic method for the treatment of HUA.

Keywords: Gegen Qinlian decoction; NLRP3; apoptosis; hyperuricemia; pharmacological network analysis.