IL‐6 initiated cis‐signaling in cultured podocytes causes glomerular injury

Abstract

The incidence of chronic kidney disease (CKD) parallels the global increase in obesity, diabetes and hypertension that characterize metabolic syndrome‐ a state of systemic inflammation. Glomerular dysfunction in CKD is marked by the loss of unique structure and function of podocytes in the glomerular filtration barrier. We hypothesized that IL‐6, an indicator of systemic inflammation, alters glomerular filtration barrier structure and function in a paracrine manner. Results show that IL‐6 (rIL‐6, 1–100pg/mL, 15min) alters glomerular barrier function demonstrated by increased glomerular albumin permeability (Palb) of isolated rat glomeruli using videomicroscopy. Increase in Palb (P<0.001, IL‐6 10pg/mL vs. Control) was blocked by α‐IL‐6 antibody. Expression of IL‐6 receptor components IL6‐Rα and gp130 in podocytes was established by immunoblotting and RT‐PCR. IL‐6 (100pg/mL, 15 min)‐induced signaling resulted in down‐regulation of ERK 1/2 phosphorylation (MAPK pathway) without an effect on Akt phosphorylation (PI3K‐Akt pathway). Finally, IL‐6 (1pg‐1ng/mL, 1hr)‐induced change in cell structure was demonstrated by confocal microscopy showing altered actin filaments and adhesion complexes in phalloidin (rhodamine) stained cells. We propose that increased IL‐6 contributes to podocyte injury observed in CKD through cellular IL‐6Rα and IL‐6Rα‐mediated cis‐signaling.