ASK-1 activation exacerbates kidney dysfunction via increment of glomerular permeability and accelerates cellular aging in diabetic kidney disease model mice

• Published in: Scientific reports 2024-11, Vol.14 (1), p.26438-12, Article 26438
• Main Authors: Kajimoto, Eriko, Nagasu, Hajime, Takasu, Masanobu, Kishi, Seiji, Wada, Masafumi, Tatsugawa, Rie, Hirano, Akira, Iwakura, Tsukasa, Umeno, Reina, Wada, Yoshihisa, Itano, Seiji, Kadoya, Hiroyuki, Kidokoro, Kengo, Sasaki, Tamaki, Kashihara, Naoki
• Format: Article
• Language: English
• Subjects: 692/4022/1585/104; 692/4022/1585/3182; Aging; Animal models; Animals; Apoptosis; Cell activation; Cellular Senescence; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease Models, Animal; Endothelial cells; Fibrosis; Glomerulus; Humanities and Social Sciences; Kidney diseases; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidneys; Male; MAP kinase; MAP Kinase Kinase Kinase 5 - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Permeability; Phenotypes; Reactive oxygen species; Reactive Oxygen Species - metabolism; Renal function; Science; Science (multidisciplinary); Senescence
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-77577-2

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD.