| First Author | Belghasem M | Year | 2023 |
| Journal | Am J Pathol | Volume | 193 |
| Issue | 10 | Pages | 1501-1516 |
| PubMed ID | 37676196 | Mgi Jnum | J:341228 |
| Mgi Id | MGI:7532221 | Doi | 10.1016/j.ajpath.2023.06.018 |
| Citation | Belghasem M, et al. (2023) Tryptophan Metabolites Target Transmembrane and Immunoglobulin Domain-Containing 1 Signaling to Augment Renal Tubular Injury. Am J Pathol 193(10):1501-1516 |
| abstractText | Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins and renal tubular damage. Tryptophan-derived uremic toxins [indoxyl sulfate (IS) and kynurenine (Kyn)] are well-characterized tubulotoxins. Emerging evidence suggests that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) protects tubular cells and promotes survival. However, the direct molecular mechanism(s) underlying how these two opposing pathways crosstalk remains unknown. We posited that IS and Kyn mediate tubular toxicity through TMIGD1 and the loss of TMIGD1 augments tubular injury. Results from the current study showed that IS and Kyn suppressed TMIGD1 transcription in tubular cells in a dose-dependent manner. The wild-type CCAAT enhancer-binding protein beta (C/EBPbeta) enhanced, whereas a dominant-negative C/EBPbeta suppressed, TMIGD1 promoter activity. IS down-regulated C/EBPbeta in primary human renal tubular cells. The adenine-induced CKD, unilateral ureteric obstruction, and deoxycorticosterone acetate salt unilateral nephrectomy models showed reduced TMIGD1 expression in the renal tubules, which correlated with C/EBPbeta expression. C/EBPbeta levels negatively correlated with the IS and Kyn levels. Inactivation of TMIGD1 in mice significantly lowered acetylated tubulin, decreased tubular cell proliferation, caused severe tubular damage, and worsened renal function. Thus, the current results demonstrate that TMIGD1 protects renal tubular cells from renal injury in different models of CKD and uncovers a novel mechanism of tubulotoxicity of tryptophan-based uremic toxins. |
