Effect of Interleukin 6 Deficiency on Renal Interstitial Fibrosis

Yang, Jun; Chen, Jiyuan; Yan, Jingyin; Zhang, Liping; Chen, Gang; He, Liqun; Wang, Yanlin

doi:10.1371/journal.pone.0052415

Cited by 46 publications

(42 citation statements)

References 37 publications

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“…CD45 and CD206 are the markers of hematopoietic cells, and PDGFR-β is a mesenchymal marker. A previous study showed that bone marrow-derived fibroblasts contributed significantly to the development of renal fibrosis [41]. In the present study, we showed that PTEN activity had a pathologically important effect on recruiting myeloid fibroblasts into the kidney and proliferation of interstitial fibroblasts in the kidney during renal fibrosis.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

Zhou

Zhong

Shi

et al. 2017

Cell Physiol Biochem

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Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

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Section: Discussionsupporting

confidence: 63%

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

Zhou

Zhong

Shi

et al. 2017

Cell Physiol Biochem

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“…For UUO model, male WT and IL-4Rα KO mice were anesthetized by intraperitoneal injection of ketamine and xylazine. Through a flank incision, the left ureter was exposed and completely ligated using fine suture material (4-0 silk) at two points as described 9, 13, 14, 42–44 .…”

Section: Methodsmentioning

confidence: 99%

The IL-4 receptor α has a critical role in bone marrow–derived fibroblast activation and renal fibrosis

Liu

Zhang

Yan

et al. 2017

Kidney International

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Renal fibrosis is a common pathway leading to the progression of chronic kidney disease and bone marrow derived fibroblasts contribute significantly to the development of renal fibrosis. However, the signaling mechanisms underlying the activation of these fibroblasts are not completely understood. Here, we examined the role of IL-4 receptor α (IL-4Rα) in the activation of myeloid fibroblasts in two experimental models of renal fibrosis. Compared with wild-type mice, IL-4Rα knockout mice accumulated fewer bone marrow derived fibroblasts and myofibroblasts in their kidneys. IL-4Rα deficiency suppressed the expression of α-smooth muscle actin, extracellular matrix proteins and the development of renal fibrosis. Furthermore, IL-4Rα deficiency inhibited the activation of signal transducer and activator of transcription 6 (STAT6) in the kidney. Moreover, wild-type mice engrafted with bone marrow cells from IL-4Rα knockout mice exhibited fewer myeloid fibroblasts in the kidney and displayed less severe renal fibrosis following ureteral obstructive injury compared with wild-type mice engrafted with wild-type bone marrow cells. In vitro, IL-4 activated STAT6 and stimulated expression of α-smooth muscle actin and fibronectin in mouse bone marrow monocytes. This was abolished in the absence of IL-4Rα. Thus, IL-4Rα plays an important role in bone marrow-derived fibroblast activation resulting in extracellular matrix protein production and fibrosis development. Hence, the IL-4Rα/STAT6 signaling pathway may serve as a novel therapeutic target for chronic kidney disease.

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“…The UUO procedure was performed as described. 6,7,17,42,43 Bone Marrow Transplantation Bone marrow transplantation was performed as previously described. 6,10,17,42,44 Briefly, bone marrow cells (5310 6 ) from WT or STAT6 KO mice were transferred to lethally irradiated WT mice.…”

Section: Animals and Uuo Surgerymentioning

confidence: 99%

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

Yan

Zhang

Yang

et al. 2015

Journal of the American Society of Nephrology

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125

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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.

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Effect of Interleukin 6 Deficiency on Renal Interstitial Fibrosis

Cited by 46 publications

References 37 publications

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

The IL-4 receptor α has a critical role in bone marrow–derived fibroblast activation and renal fibrosis

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

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