JAK3/STAT6 Stimulates Bone Marrow–Derived Fibroblast Activation in Renal Fibrosis

Abstract

Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/ signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrowderived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of a-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose-dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6 2/2 bone marrow cells displayed fewer bone marrow-derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild-type mice engrafted with STAT6 +/+ bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow-derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development.

T Helper 2 Cytokine Signaling in Bone Marrow–Derived Fibroblasts

“…19 A recent study has revealed that the TGF-b1-Smad3 pathway induces the transition of monocytes to bone marrow-derived fibroblasts in the course of renal fibrosis. 20 Yan et al 17 showed in this study that TGF-b1-induced expression of aSMA, fibronectin, and COLI was not affected by the pretreatment with CP690550 in rat kidney fibroblasts. These results indicate that the effect of CP690550 on the transition of monocytes to bone marrow-derived fibroblasts could be independent of the TGF-b1-Smad3 pathway; however, an experiment using TGF-b1-treated bone marrow-derived monocytes and CP690550 will be required to clarify it.…”

“…In this issue of JASN, Yan et al 17 clarified the importance of Janus kinase 3 (JAK3) -signal transducer and activator of transcription 6 (STAT6) signaling in the pathogenesis of renal fibrosis through the activation of bone marrow-derived fibroblasts. Yan et al 17 showed that IL-4 or IL-13 stimulated bone marrow-derived monocytes to express aSMA and extracellular matrix, such as COLI and fibronectin, suggesting that bone marrow-derived monocytes could differentiate into bone marrow-derived fibroblasts (COLI 1 ) and myofibroblasts (COLI 1 /aSMA 1 ) in response to Th2 cytokines IL-4 or IL-13.…”

“…Yan et al 17 showed that IL-4 or IL-13 stimulated bone marrow-derived monocytes to express aSMA and extracellular matrix, such as COLI and fibronectin, suggesting that bone marrow-derived monocytes could differentiate into bone marrow-derived fibroblasts (COLI 1 ) and myofibroblasts (COLI 1 /aSMA 1 ) in response to Th2 cytokines IL-4 or IL-13. JAK3 inhibitor CP690550 (tofacitinib) suppressed IL-4-or IL-13-induced expression of aSMA and extracellular matrix as well as phosphorylation of STAT6 in bone marrowderived monocytes.…”

“…21 Yan et al 17 investigated the role of JAK3-STAT6 signaling in UUO-induced renal fibrosis as well. CP690550 administration or STAT6 deficiency significantly attenuated renal fibrosis as estimated by renal amounts of collagen and aSMA.…”

“…Several studies 22,23 have shown that JAK3 is also expressed in epithelial cells, including those in the kidney, and JAK3 signaling is thought to be involved in renal phosphate metabolism through 25-hydroxyvitamin D 1a-hydroxylase expression. 24 To clarify the importance of bone marrow JAK3-STAT6 signaling in the pathogenesis of renal fibrosis, Yan et al 17 bone marrow cells showed fewer bone marrow-derived fibroblasts and a lesser degree of renal collagen content. These data indicate that JAK3-STAT6 signaling in bone marrow cells has a fundamental role in the development of renal fibrosis through accumulation of bone marrow-derived fibroblasts/myofibroblasts.…”