Uremic toxin indoxyl sulfate induces dysfunction of vascular smooth muscle cells via integrin-β1/ERK signaling pathway

• Published in: Clinical and experimental nephrology Vol. 26; no. 7; pp. 640 - 648
• Main Authors: Yu, Haibo, Zhou, Chunyu, Hu, Dayong, Li, Changbin, Wang, Qiang, Xue, Wen, Peng, Ai
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.07.2022; Springer Nature B.V
• Subjects: Apoptosis; Cardiovascular diseases; Cell proliferation; Endothelial cells; Extracellular signal-regulated kinase; Kidney diseases; Kinases; Medicine; Medicine & Public Health; Nephrology; Original Article; RNA-mediated interference; Signal transduction; Smooth muscle; Sulfates; Therapeutic targets; Umbilical vein; Urology; Extracellular signal-regulated kinase; Smooth muscle cells; Protein-bound uremic toxins; Integrin-β1; Indoxyl sulfate
• ISSN: 1342-1751; 1437-7799; 1437-7799
• DOI: 10.1007/s10157-022-02195-z

Background Protein-bound uremic toxins (PBUTs) are reported to be one of the major culprits in chronic kidney disease–cardiovascular disease (CKD–CVD) development, yet its mechanism is not fully clear. Our previous study confirmed elevated expression of integrin-β1 (ITGβ1) in vascular smooth muscle cells of uremic patients. Thus, this study aimed to explore the relationship between PBUTs and ITGβ1 in uremic vasculature injury. Methods Human umbilical vein smooth muscle cells (HUVSMCs) and endothelial cells (HUVECs) were treated with two representative PUBTs, indoxyl sulfate (IS) and p -cresyl sulfate (PC). Both cells were measured for the expression of ITGβ1 and downstream signaling pathways and assayed for proliferation, migration, adhesion and apoptosis. Results The IS treatments were observed with significantly up-regulated ITGβ1 in HUVSMCs but not in HUVECs, while PC did not induce ITGβ1 alteration in either HUVSMCs or HUVECs. Furthermore, overexpression of ITGβ1 revealed activated downstream signal-regulated kinase (ERK) signaling pathway with promoted focal adhesion, migration, proliferation but no apoptosis in HUVSMCs by IS. These functional and pathway alterations could be significantly suppressed by RNA interference of ITGβ1. More importantly, the application of ERK1/2 inhibitor significantly suppressed the focal adhesion, migration and proliferation of HUVSMCs. Conclusion We first demonstrated that ITGβ1/ERK signaling pathway mediated abnormal focal adhesion, migration and proliferation of vascular smooth muscle cells stimulated by IS. ITGβ1/ERK signaling may serve as a novel therapeutic target for CKD-CVD.