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Surprisingly, tubulo\u2010interstitial fibrosis (TIF), does not develop significantly until the late stage of DKD. Here, it is demonstrated that PR domain\u2010containing 16 (PRDM16) is a key to the low level of TIF in DKD. In the experiments, PRDM16 is upregulated in high glucose\u2010treated renal tubular cells, DKD mouse kidneys, and renal biopsy of human DKD patients via activation of NF\u2010\u03baB signal pathway. High glucose\u2010induced expression of fibrotic proteins in renal tubular cells is suppressed by PRDM16. Mechanistically, PRDM16 bound to the promotor region of Transient receptor potential ankyrin 1 (TRPA1) to transactivate its expression and then suppressed MAPK (P38, ERK1\/2) activation and downstream expression of TGF\u2010\u03b21. Knockout of PRDM16 from kidney proximal tubules in mice blocked TRPA1 expression and enhanced MAPK activation, TGF\u2010\u03b21 production, TIF development, and DKD progression, whereas knock\u2010in of PRDM16 has opposite effects. In addition, overexpression of PRDM16 or its induction by formononetin ameliorated renal dysfunction and fibrosis in db\/db diabetic mice. Finally, the above finding are detected in renal biopsies of DKD patients. Together, these results unveil PRDM16\/TRPA1 as the mechanism responsible for the low level of TIF in the early stage of DKD by suppressing and TGF\u2010\u03b21 expression.<\/jats:p>","DOI":"10.1002\/advs.202306704","type":"journal-article","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T21:46:18Z","timestamp":1702244778000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Discovery of PRDM16\u2010Mediated TRPA1 Induction as the Mechanism for Low Tubulo\u2010Interstitial Fibrosis in Diabetic Kidney Disease"],"prefix":"10.1002","volume":"11","author":[{"given":"Fang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine Second Xiangya Hospital Central South University  Changsha Hunan 410011 P. R. China"},{"name":"Emergency Medicine and Difficult Diseases Institute Second Xiangya Hospital Central South University  Changsha Hunan 410011 P. R. 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