Hydroxychloroquine ameliorates immune functionality and intestinal flora disorders of IgA nephropathy by inhibition of C1GALT1/Cosmc pathway

Abstract

Background

Hydroxychloroquine (HCQ) has emerged as a potential and secure antiproteinuric agent in IgA nephropathy (IgAN). This study endeavored to explore the impact of HCQ on the immune functionality and intestinal flora disorders in IgAN rats, as well as to elucidate the underlying mechanisms through in vivo and in vitro experiments.

Methods

IgAN model was established in Sprague-Dawley rats through the administration of BSA, LPS, and CCl₄, and the IgAN rats received a continuous 8-week treatment with HCQ. Moreover, the human glomerular mesangial cells (HMCs) were incubated with IgA1 to establish an in vitro cellular model of IgAN. At the end of experimental period, samples were collected for further analysis.

Results

HCQ ameliorated the elevated levels of 24hUTP, SCr, BUN, the number of urinary RBC, and the activation of inflammation-related proteins within the TLR4/NF-κB signaling pathway. In the IgAN rat group, there was a pronounced escalation in IgA deposition, mesangial matrix hyperplasia, and glomerular inflammatory cell infiltration, while the administration of HCQ effectively mitigated these pathological changes. In addition, the reduced production of CD4⁺CD25⁺Foxp3⁺ Treg in the IgAN group was effectively reversed by HCQ. Furthermore, HCQ has the capacity to restore the compromised state of the intestinal mucosal barrier induced by IgAN and mitigate the circumstances of intestinal permeability and disruption in the intestinal flora.

Conclusion

HCQ diminishes IgA aberrant glycosylation levels, ameliorates renal and intestinal histopathological damage, and attenuates intestinal flora disorders and immune dysfunction in IgAN rats by means of activating the C1GALT1/Cosmc pathway.

Keywords:

• Hydroxychloroquine
• immunoglobulin A nephropathy
• intestinal flora
• immune functionality
• C1GALT1/cosmc pathway

Authors’ contributions

Conceptualization ideas, Chaochao Wang; validation verification, Chaochao Wang and Xiaoqiao Cai; formal analysis, Chaochao Wang and Shengfen Lin; investigation, Xiaoqiao Cai and Shengfen Lin; data curation, Xiaoqiao Cai and Shengfen Lin; writing - original draft preparation, Chaochao Wang; writing - review & editing, Yongqiang Lin; visualization preparation, Yongqiang Lin; funding acquisition, Chaochao Wang. All authors have read and agreed to the published version of the manuscript.

Ethics approval

All animal experiments were approved by Wenzhou Medical University Laboratory Animal Ethics Committee (xmsq2021-0500) and the National Research Council’s Guide for the Care and Use of Laboratory Animals; The study is reported in accordance with ARRIVE guidelines (https://arriveguidelines.org) and Basel Declaration (http://www.basel-declaration.org/basel-declaration/). The euthanasia method in this study was informed by the American Veterinary Medical Association (AVMA) Guidelines for the Euthanasia of Animals (2020).

Consent for publication

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

Data will be made available from corresponding author upon reasonable request.

Additional information

Funding

This work was supported by Zhejiang Medical and Health Science and Technology Plan Project (Grant number: 2022KY1208).