Tribbles pseudokinase 3 promoted renal fibrosis by regulating the expression of DNA damage-inducible transcript 3 in diabetic nephropathy

Lulu Kong; Liusha Kong; Peipei Li; Li Gao; Hongqin Ma; Bimin Shi

doi:10.17305/bb.2024.10419

Authors

Lulu Kong Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, China; Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Liusha Kong Department of Nephrology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Peipei Li Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Li Gao Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Hongqin Ma Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
Bimin Shi Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, China

DOI:

https://doi.org/10.17305/bb.2024.10419

Keywords:

Diabetic nephropathy (DN), tribbles pseudokinase 3 (TRIB3), DNA damage inducible transcript 3 (DDIT3), inflammatory response, extracellular matrix (ECM) accumulation

Abstract

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB, among differentially expressed genes (DEGs) in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production inMPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.