Abstract
Lupus nephritis (LN) constitutes the most common organ-threatening manifestation of systemic lupus erythematosus (SLE), with the pathological proliferation of mesangial cells (MCs) recognized as a critical factor in its pathogenesis and progression. Self-DNA-containing immune complex (DNA-IC) represents a prime pathogenic factor in SLE, yet its pathological effect on MCs remains unclear. In the present study, we elucidated the mechanism underlying the excessive proliferation of MCs following the recognition of DNA-IC in patients with LN. Here, we pinpointed that the excessive proliferation of MCs was attributed to an anomalous transition from the G1 to the S phase of the cell cycle in patients with LN. Mechanically, the dysfunction of P27 protein resulted in the aberrant G1-S phase transition, and the phenomenon was closely related to the ubiquitin-mediated degradation of its key transcription factor, PBX1. This degradation was regulated by lactylation of PBX1 in the site of Lys40 residue. The elevated lactylation level of PBX1 protein was caused by the upregulation of glycolysis levels induced by DNA-IC. Accordingly, targeting lactate production in MCs from patients with LN effectively alleviated their renal inflammation and fibrosis progression. Elevated lactate resulted in PBX1 lactylation, leading to excessive proliferation of MCs and, thus, serving as a promising therapeutic target for LN.
Authors
Enzhuo Liu, Chenghua Weng, Chenchu Yan, Xingchen Zhu, Xinyue Li, Mengdi Liu, Zhenke Wen, Zhichun Liu
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
