Tubular cell transcriptional intermediary factor 1y deficiency exacerbates kidney injury-induced tubular cell and fibrosis

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 1y (TIF1y) inhibits the progression of fibrosis in other organs. Here, we found that TIF1y was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1y 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 TIF1y in mice exacerbated UUO-and FAN-induced tubular cell polyploidy and subsequent fibrosis, whereas overexpression of kidney TIF1y protected mice against kidney fibrosis. Mechanistically, in tubular epithelial cells, TIF1y exerted an antifibrotic role via transforming growth factor-D (TGF-D)-dependent and-independent signaling. TIF1y hindered TGF-D signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular cells, and we discovered that TIF1y suppressed epidermal growth factor receptor (EGFR) signaling upstream of TGF-D signaling in tubular cells by ubiquitylating EGFR at its lysine 851/905 sites thereby promoting EGFR internalization and lysosomal degradation. Pharmacological inhibition of EGFR signaling attenuated exacerbated polyploidization and the fibrotic phenotype in mice with tubule deletion of TIF1y. Thus, tubular TIF1y plays an important role in kidney fibrosis by suppressing profibrotic EGFR and TGF-D signaling. Hence, our findings suggest that maintaining homeostasis of tubular TIF1y may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD.