Olmesartan alleviates SARS-CoV-2 envelope protein induced renal fibrosis by regulating HMGB1 release and autophagic degradation of TGF-β1

Shilin Zhou; Zanzhe Yu; Zihui Chen; Fengling Ning; Xuetao Hu; Tiangang Wu; Mingxue Li; Hong Xin; Svetlana Reilly; Xuemei Zhang

doi:10.3389/fphar.2023.1187818

Olmesartan alleviates SARS-CoV-2 envelope protein induced renal fibrosis by regulating HMGB1 release and autophagic degradation of TGF-β1

Front Pharmacol. 2023 May 15:14:1187818. doi: 10.3389/fphar.2023.1187818. eCollection 2023.

Authors

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
² Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³ School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁴ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.

Abstract

Background and aims: Renal damage in severe coronavirus disease 2019 (COVID-19) is highly associated with mortality. Finding relevant therapeutic candidates that can alleviate it is crucial. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have been shown to be harmless to COVID-19 patients, but it remains elusive whether ACEIs/ARBs have protective benefits to them. We wished to determine if ACEIs/ARBs had a protective effect on the renal damage associated with COVID-19, and to investigate the mechanism. Methods: We used the envelope (E) protein of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to induce COVID-19-like multiple organ damage and observed renal fibrosis. We induced the epithelial-mesenchymal transformation of HK-2 cells with E protein, and found that olmesartan could alleviate it significantly. The protective effects of olmesartan on E protein-induced renal fibrosis were evaluated by renal-function assessment, pathologic alterations, inflammation, and the TGF-β1/Smad2/3 signaling pathway. The distribution of high-mobility group box (HMGB)1 was examined after stimulation with E protein and olmesartan administration. Results: E protein stimulated HMGB1 release, which triggered the immune response and promoted activation of TGF-β1/Smad2/3 signaling: both could lead to renal fibrosis. Olmesartan regulated the distribution of HMGB1 under E protein stimulation. Olmesartan inhibited the release of HMGB1, and reduced the inflammatory response and activation of TGF-β1/Smad2/3 signaling. Olmesartan increased the cytoplasmic level of HMGB1 to promote the autophagic degradation of TGF-β1, thereby alleviating fibrosis further. Conclusion: Olmesartan alleviates E protein-induced renal fibrosis by regulating the release of HMGB1 and its mediated autophagic degradation of TGF-β1.

Keywords: HMGB1; SARS-CoV-2; TGF-β1; autophagy; envelope protein; olmesartan; renal fibrosis.

Grants and funding

This research was supported by the Science and Technology Innovation Plan of Shanghai Science and Technology Commission (No. 20410713300, China) and the National Natural Science Foundation of China (No. 81973385).