Gp130-dependent signaling in the podocyte

Abstract

Renal inflammation, in particular glomerular, is often characterized by increased IL-6 levels. The in vivo relevance of IL-6 signaling in glomerular podocytes, which play central roles in most glomerular diseases, is unknown. Here, we show that in normal mice, podocytes express gp130, the common signal-transducing receptor subunit of the IL-6 family of cytokines. Following systemic IL-6 or LPS injection in mice, podocyte IL-6 signaling was evidenced by downstream STAT3 phosphorylation. Next, we generated mice deficient for gp130 in podocytes. Expectedly, these mice exhibited abrogated IL-6 downstream signaling in podocytes. At the age of 40 wk, they did not show spontaneous renal pathology or abnormal renal function. The mice were then challenged using two LPS injury models as well as nephrotoxic serum to induce crescentic nephritis. Under all conditions, circulating IL-6 levels increased markedly and the mice developed the pathological hallmarks of the corresponding injury models such as proteinuria and development of glomerular crescents, respectively. However, despite the capacity of normal podocytes to transduce IL-6 family signals downstream, there were no significant differences between mice bearing the podocyte-specific gp130 deletion and their control littermates in any of these models. In conclusion, under the different conditions tested, gp130 signaling was not a critical component of the (patho-)biology of the podocyte in vivo.

IL-6 Trans-Signaling Drives Murine Crescentic GN

“…Bioactivity against IL-6 in vivo of this antibody and the batch used was evidenced previously by us and others. 4,27,28 Selective Inhibition of Trans-Signaling Improves the Course of NTN in BALB/c Mice Next we assessed the effects of selective blockade of IL-6 transsignaling with sgp130Fc in NTN ( Figure 5, left panels). sgp130Fc injections started after disease induction, i.e., in a therapeutic manner and in an attempt to avoid interference with disease induction.…”

“…4 See Table 1 for primary antibody specifications. Analyses were performed in a blinded fashion as described.…”

“…Analyses were performed in a blinded fashion as described. 4 In brief, 100 Periodic acid-Schiff-stained glomeruli and 20 anti-CD3-stained glomerular cross-sections were evaluated per mouse. F4/80 was quantified using software as percent of total area.…”

“…4 The corresponding primary antibodies and primer sequences are listed in Tables 1 and 2, respectively.…”

“…[1][2][3][4][5] It is mostly produced by leukocytes but can also be secreted from glomerular endothelial and mesangial cells upon stimulation with, for example, angiotensin II and by podocytes following endotoxin administration in vivo. [6][7][8] However, the role of IL-6 signaling in glomerular disease, in particular in rapidly progressive glomerulonephritis (RPGN), remains controversial.…”