Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction

• We investigated the role of JAK/STAT/SOCS pathway in renal fibrosis in UUO.
• Renal fibrosis was suppressed in SOCS3+/- mice and aggravated by JAK inhibitor.
• SOCS deficiency-activated JAK/STAT didn’t alter profibrotic cytokines, but MMP-2.
• JAK/STAT3 signaling may play an important role in repair process of renal fibrosis.

Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3+/− mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6–PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3+/− mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3+/− mice, while it was aggravated by pre-treatment with pyridine6–PGLA. Although there were no differences in renal mRNA levels of TGF-β and collagens between wild and SOCS3+/− mice, MMP-2 activity was enhanced in SOCS3+/− UUO mice. Activated MMP-2 was completely suppressed by pyridine6–PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.