Tubular Cell Transcriptional Intermediary Factor 1γ Deficiency Exacerbates Kidney Injury-Induced Tubular Cell Polyploidy and Fibrosis

Jul 10, 2026

Tubulointerstitial fibrosis is the convergent endpoint of progressive chronic kidney diseases, yet mechanisms after kidney injury remain unclear. Reduced expression of tubular transcriptional intermediary factor 1g (TIF1g) is detected in CKD patients and in mouse models of experimental kidney fibrosis. Tubule-specific TIF1g knockout worsens tubular cell polyploidy and subsequent fibrosis, while TIF1g overexpression protects against fibrotic injury. Mechanistically, TIF1g suppresses pro-fibrotic EGFR signaling by ubiquitylating EGFR and thereby restraining TGF-β/Smad signaling in tubular epithelial cells.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

Background and Rationale

Expression Changes in CKD and Animal Models

Genetic Manipulation Effects on Polyploidy and Fibrosis

Mechanistic Pathways (TGF-β/Smad, EGFR Ubiquitylation)

Therapeutic Implications and Translational Statement

[www.kidney-international.org](www.kidney-international.org basic)[ basic](www.kidney-international.org basic) research Tubular cell transcriptional intermediary factor 1g deﬁciency exacerbates kidney injury-induced tubular cell polyploidy and ﬁbrosis Chaoyi Yuan 1, 10, Guannan Jin2, 10, Pengcheng Li 1, 10, Wei Wang 1, 10, Chang Ge3, Yonglong Pan 1, Qiaofeng Zhang 1, Jie Mo 1, Dong Kuang4, Liu Liu5, Xuewu Zhang 1, Huifang Liang 1, Wanguang Zhang 1, Xi Tang6, Zifu Li7, Jihong Liu8, Gang Xu5, Xiaoping Chen 1,9, Ze-yang Ding 1 and Bixiang Zhang 1 1Department of Surgery, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of HepatoPancreatic-Biliary Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 3Department of Nephrology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4Department of Pathology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 5Department of Nephrology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 6Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China; 7National Engineering Research Center for Nanomedicine, Department of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; 8Department and Institute of Urology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and 9Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission, Wuhan, China Tubulointerstitial ﬁbrosis is considered the ﬁnal convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms underlying kidney injury-induced ﬁbrosis largely remain unknown. Recent studies have indicated that transcriptional intermediary factor 1g (TIF1g) inhibits the progression of ﬁbrosis in other organs. Here, we found that TIF1g was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1g expression was decreased in patients with CKD, including those with diabetes, hypertension, and IgA nephropathy, and in mouse models with experimental kidney ﬁbrosis (unilateral ureteral obstruction [UUO], folic acid nephropathy [FAN], and aristolochic acid-induced nephrotoxicity). Tubule-speciﬁc knock out of TIF1g in mice exacerbated UUO-and FAN-induced tubular cell polyploidy and subsequent ﬁbrosis, whereas overexpression of kidney TIF1g protected mice against kidney ﬁbrosis. Mechanistically, in tubular epithelial cells, TIF1g exerted an antiﬁbrotic role via transforming growth factor-b (TGF-b) -dependent and-independent signaling. TIF1g hindered TGF-b signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular Correspondence: Bixiang Zhang, Ze-yang Ding, and Xiaoping Chen, Department of Surgery, and Gang Xu, Department of Nephrology, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. E-mail: [bixiangzhang@hust.edu.cn](bixiangzhang@hust.edu.cn), [zyding@tjh.tjmu.edu.cn](zyding@tjh.tjmu.edu.cn), chenxp@ [tjh.tjmu.edu.cn](tjh.tjmu.edu.cn) [and xugang@tjh.tjmu.edu.cn](and xugang@tjh.tjmu.edu.cn) 10CY, GJ, PL, and WW contributed equally to this work. Received 2 October 2022; revised 4 July 2023; accepted 14 July 2023; published online 22 July 2023

FAQs

What is the central finding about TIF1g in kidney fibrosis?

Reduced tubular TIF1g expression worsens kidney injury outcomes by promoting tubular cell polyploidy and accelerating fibrotic progression, whereas maintaining or increasing TIF1g expression is protective.

How does TIF1g influence tubular cell polyploidy and fibrosis?

Tubule-specific loss of TIF1g exacerbates polyploidization followed by fibrosis in proximal tubular cells, and pharmacologic EGFR inhibition attenuates these exacerbated phenotypes.

Through which signaling mechanisms does TIF1g exert its anti-fibrotic role?

In tubular epithelial cells, TIF1g suppresses pro-fibrotic signaling by inhibiting TGF-β signaling and by acting upstream of TGF-β through EGFR ubiquitylation at lysine 851/905, promoting EGFR internalization and lysosomal degradation.

Jul 10, 2026

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