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Correlating Gene-specific DNA Methylation Changes with Expression and Transcriptional Activity of Astrocytic KCNJ10 Kir4.1
Published on: September 26, 2015
Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis
Ayaha Yamamoto1, Hitomi Morioki1, Takafumi Nakae1
1Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Abstract:
Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP responsive element-binding protein 3-like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS-expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF-β1 increased OASIS expression coincident with fibroblast-to-myofibroblast transition and OASIS contributed to TGF-β1-mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti-Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast-restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.
Insights
Old astrocyte specifically induced substance (OASIS) promotes kidney fibrosis by increasing myofibroblast activity and Bone marrow stromal antigen 2 (Bst2) expression. Targeting OASIS offers a novel therapeutic strategy for chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Kidney fibrosis is a key pathological process in chronic kidney disease (CKD).
- Identifying novel therapeutic targets for kidney fibrosis is crucial for effective CKD management.
- The role of Old astrocyte specifically induced substance (OASIS) in kidney fibrosis was previously unknown.
Purpose of the Study:
- To investigate the role of OASIS/cAMP responsive element-binding protein 3-like 1 (CREB3l1) in kidney fibrosis.
- To determine if OASIS is a profibrotic gene and a potential therapeutic target in CKD.
Main Methods:
- Immunohistochemistry to assess OASIS protein expression in human and murine fibrotic kidneys.
- In vitro assays to evaluate the effect of TGF-β1 on OASIS expression and myofibroblast behavior.
- In vivo studies using systemic OASIS genetic knockout and myofibroblast-restricted conditional knockout mouse models.
- Analysis of Bone marrow stromal antigen 2 (Bst2) expression in OASIS knockout models.
- In vivo administration of anti-Bst2 blocking antibody.
Main Results:
- OASIS protein was significantly overexpressed in human and murine fibrotic kidneys, particularly in myofibroblasts.
- Exogenous TGF-β1 upregulated OASIS expression, promoting fibroblast-to-myofibroblast transition, migration, and proliferation.
- Systemic knockout of OASIS ameliorated kidney fibrosis induced by unilateral ureteral obstruction (UUO) or ischemia/reperfusion injury.
- OASIS knockout reduced myofibroblast proliferation and decreased Bst2 expression.
- Targeting Bst2 attenuated kidney fibrosis in normal mice but not in OASIS knockout mice, indicating Bst2 acts downstream of OASIS.
- Myofibroblast-specific OASIS knockout conferred resistance to kidney fibrosis.
Conclusions:
- OASIS is a novel profibrotic gene that promotes kidney fibrosis by enhancing myofibroblast activity.
- OASIS signaling, at least in part through increased Bst2 expression, drives kidney fibrosis.
- OASIS represents a promising therapeutic target for preventing and treating kidney fibrosis in CKD.
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