Inhibitory effect of tumor necrosis factor‑α on the basolateral Kir4.1/Kir5.1 channels in the thick ascending limb during diabetes

• Published in: Experimental and therapeutic medicine 2021-11, Vol.22 (5), Article 1242
• Main Authors: Zhang, Guoyan, Lv, Zhiming, Zhao, Yang, Chen, Rui, Zhan, Xiangyu, Wang, Weiqun, Sui, Hongyu
• Format: Article
• Language: English
• Subjects: Antibodies; Cytokines; Diabetes; Diabetic nephropathy; Glucose; Kidneys; Membranes; Metabolism; Necrosis; Protein expression; Proteins; Rodents; Software; Statistical analysis; Tumor necrosis factor-TNF; Urine
• ISSN: 1792-0981; 1792-1015
• DOI: 10.3892/etm.2021.10677

Diabetic nephropathy is a major contributor to the morbidity and mortality of patients with diabetes. TNF-α expression is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy; however, its underlying molecular mechanisms remain unclear. The present study aimed to investigate the effect and molecular mechanism of TNF-α on the basolateral inwardly rectifying potassium (Kir)4.1/Kir5.1 channels in the thick ascending limb (TAL) of rat kidneys using western blotting and the patch clamp technique to provide a theoretical basis for the cause of the decrease in kidney concentrating capacity during diabetes. The results demonstrated that urinary TNF-α excretion and protein TNF-α expression in the TAL increased and basolateral Kir4.1/Kir5.1 channel activity decreased during diabetes; however, diabetic rats exhibited amelioration of Kir4.1/Kir5.1 activity with a soluble TNF-α antagonist, TNF receptor fusion protein (TNFR:Fc). These results suggested that TNF-α inhibited the activity of the basolateral Kir4.1/Kir5.1 channel in the TAL of rat kidneys during diabetes. In addition, the protein expression levels of phospholipase A2 (PLA2) and cyclooxygenase-2 (COX2) increased in diabetic rats, the effects of which deceased following treatment with TNFR:Fc compared with the diabetic group. Furthermore, an agonist of PLA2 (melittin) and COX2 production [prostaglandin E2 (PGE2)] inhibited the basolateral Kir4.1/Kir5.1 channels. Taken together, the results of the present study suggested that the inhibitory effect of TNF-α on the basolateral Kir4.1/Kir5.1 channels in the TAL during diabetes is mediated by the PLA2/COX2/PGE2 signaling pathway.