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

Kiyomi Koike; Seiji Ueda; Sho-ichi Yamagishi; Hideo Yasukawa; Yusuke Kaida; Miyuki Yokoro; Kei Fukami; Akihiko Yoshimura; Seiya Okuda

doi:10.1016/j.clim.2013.11.003

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

Clin Immunol. 2014 Jan;150(1):78-87. doi: 10.1016/j.clim.2013.11.003. Epub 2013 Nov 13.

Authors

Kiyomi Koike¹, Seiji Ueda², Sho-ichi Yamagishi³, Hideo Yasukawa⁴, Yusuke Kaida², Miyuki Yokoro², Kei Fukami², Akihiko Yoshimura⁵, Seiya Okuda²

Affiliations

¹ Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. Electronic address: koike_kiyomi@kurume-u.ac.jp.
² Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
³ Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
⁴ Division of Cardio Vascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
⁵ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

PMID: 24333535
DOI: 10.1016/j.clim.2013.11.003

Abstract

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.

Keywords: JAK; MMP-2; Renal fibrosis; SOCS; STAT; UUO.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Collagen / genetics
Cytokines / genetics
Female
Fibrosis / metabolism*
Fibrosis / pathology
Humans
Janus Kinases / antagonists & inhibitors
Janus Kinases / metabolism*
Kidney / metabolism
Kidney / pathology
Kidney Diseases / metabolism*
Kidney Diseases / pathology
Kidney Tubules, Proximal / cytology
Matrix Metalloproteinase 2 / metabolism
Mice
Mice, Inbred BALB C
Mice, Transgenic
Pyridines / pharmacology
STAT3 Transcription Factor / metabolism*
Signal Transduction
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins / genetics
Tumor Necrosis Factor-alpha / pharmacology
Ureteral Obstruction / metabolism*
Ureteral Obstruction / pathology

Substances

Cytokines
Pyridines
STAT3 Transcription Factor
Socs3 protein, mouse
Stat3 protein, mouse
Suppressor of Cytokine Signaling 3 Protein
Suppressor of Cytokine Signaling Proteins
Tumor Necrosis Factor-alpha
Collagen
Janus Kinases
Matrix Metalloproteinase 2
Mmp2 protein, mouse