Inhibitory Effect Of Tumor Necrosis Factor-Alpha On The Basolateral Kir4.1/Kir5.1 Channels In The Thick Ascending Limb During Diabetes

Diabetic nephropathy is a major contributor to the morbidity and mortality of patients with diabetes. TNF-alpha 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-alpha 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-alpha excretion and protein TNF-alpha 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-alpha antagonist, TNF receptor fusion protein (TNFR:Fc). These results suggested that TNF-alpha 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 A(2) (PLA(2)) 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 PLA(2) (melittin) and COX2 production [prostaglandin E-2 (PGE(2))] inhibited the basolateral Kir4.1/Kir5.1 channels. Taken together, the results of the present study suggested that the inhibitory effect of TNF-alpha on the basolateral Kir4.1/Kir5.1 channels in the TAL during diabetes is mediated by the PLA(2)/COX2/PGE(2) signaling pathway.