GSDMD and GSDME synergy in the transition of acute kidney injury to chronic kidney disease

Zhengyue Chen; Caiming Chen; Kunmei Lai; Chengkun Wu; Fan Wu; Zhimin Chen; Keng Ye; Jingzhi Xie; Huabin Ma; Hong Chen; Yujia Wang; Yanfang Xu

doi:10.1093/ndt/gfae014

GSDMD and GSDME synergy in the transition of acute kidney injury to chronic kidney disease

Nephrol Dial Transplant. 2024 Jan 19:gfae014. doi: 10.1093/ndt/gfae014. Online ahead of print.

Authors

Zhengyue Chen¹, Caiming Chen^{1

2

3}, Kunmei Lai¹, Chengkun Wu⁴, Fan Wu¹, Zhimin Chen¹, Keng Ye¹, Jingzhi Xie¹, Huabin Ma⁵, Hong Chen⁶, Yujia Wang^{1

2

3}, Yanfang Xu^{1

2

3}

Affiliations

¹ Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
² Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
³ Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁴ School of Medicine, Nankai University, Tianjin, China.
⁵ Central Laboratory, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁶ Department of Pathology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

PMID: 38244230
DOI: 10.1093/ndt/gfae014

Abstract

Background and hypothesis: Acute kidney injury (AKI) could progress to chronic kidney disease (CKD) and the AKI-CKD transition has major clinical significance. A growing body of evidence has unveiled the role of pyroptosis in kidney injury. We postulate that GSDMD and GSDME exert cumulative effects on the AKI-CKD transition by modulating different cellular responses.

Methods: We established an AKI-CKD transition model induced by folic acid in wildtype (WT), Gsdmd-/-, Gsdme-/-, and Gsdmd-/-Gsdme-/- mice. Tubular injury, renal fibrosis and inflammatory responses were evaluated. In vitro studies were conducted to investigate the interplay among tubular cells, neutrophils, and macrophages.

Results: Double deletion of Gsdmd and Gsdme conferred heightened protection against AKI, mitigating inflammatory responses, including the formation of neutrophil extracellular traps (NETs), macrophage polarization and differentiation, and ultimately renal fibrosis, compared with wildtype mice and mice with single deletion of either Gsdmd or Gsdme. Gsdme, but not Gsdmd deficiency, shielded tubular cells from pyroptosis. GSDME-dependent tubular cell death stimulated NETs formation and prompted macrophage polarization towards a pro-inflammatory phenotype. Gsdmd deficiency suppressed NETs formation and subsequently hindered NETs-induced macrophage-to-myofibroblast transition (MMT).

Conclusion: GSDMD and GSDME collaborate to contribute to AKI and subsequent renal fibrosis induced by folic acid. Synchronous inhibition of GSDMD and GSDME could be an innovative therapeutic strategy for mitigating the AKI-CKD transition.

Keywords: GSDMD; GSDME; acute kidney injury; inflammation; renal fibrosis.