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.
Background IL-6 family cytokines play protective roles in cardiomyocytes via STAT3 activation. Glomerular podocytes, as an important component of the kidney blood filtration, are terminally ...differentiated cells as well as cardiomyocytes. Although some studies have shown that STAT3 activation is associated with podocyte dysfunction, it remains unclear whether activated STAT3 exhibits differential functions depending on cytokines. The aim of this study is to assess the effects of IL-6 family cytokines/STAT3 signaling in podocytes. Methods and results To examine the pathophysiological relevance of IL-6 family cytokines in kidney diseases, C57BL/6J mice were subjected to ischemia-reperfusion or lipopolysaccharide (LPS) treatment. Quantitative PCR demonstrated that the expression level of IL-6, leukemia inhibitory factor (LIF) and IL-11 was upregulated in injured kidneys. In cultured podocytes, STAT3 was rapidly activated in response to the stimulation with IL-6, LIF or IL-11. Interestingly, LIF and IL-11 treatment suppressed H2O2-induced cell death in cultured podocytes, whereas IL-6 tended to increase cell death. ConclusionSTAT3 could differentially function in an activator cytokine-specific manner, in podocytes, providing the important information for the development of therapy targeting STAT3 for kidney diseases.
Background Since kidney fibrosis is a common pathway to many kidney diseases, prevention of kidney fibrosis could be a therapeutic strategy for kidney diseases. Previously, we reported that old ...astrocyte specifically induced substance (OASIS), a transcription factor, promotes proliferation of renal myofibroblasts, analyzed by in vitro assay. However, the pathophysiological significance of OASIS in kidney fibrosis in vivo remains to be elucidated.Methods/Results C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) to cause kidney fibrosis, analyzed by Sirius red staining and hydroxyproline assay. AEBSF, an inhibitor of OASIS, suppressed kidney fibrosis at day 7 after UUO. Moreover, kidney fibrosis was ameliorated in OASIS KO mice compared with WT mice, accompanied by decreased proliferation of myofibroblasts. To explore the downstream of OASIS, DNA microarray was performed using myofibroblasts from OASIS KO mice. Interestingly, it was found that bone marrow stromal antigen 2 (BST2) was a candidate downstream gene of OASIS. Anti-BST2 antibody treatment attenuated UUO-induced kidney fibrosis.Conclusion OASIS contributes to the develop of kidney fibrosis by promoting the proliferation of myofibroblasts, in part, through increased BST2 expression. OASIS could be a therapeutic target against kidney fibrosis.
Background Since kidney fibrosis is a common pathway to many kidney diseases, prevention of kidney fibrosis could be a therapeutic strategy for kidney diseases. Previously, we reported that old ...astrocyte specifically induced substance (OASIS), a transcription factor, promotes proliferation of renal myofibroblasts, analyzed by in vitro assay. However, the pathophysiological significance of OASIS in kidney fibrosis in vivo remains to be elucidated.Methods/Results C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) to cause kidney fibrosis, analyzed by Sirius red staining and hydroxyproline assay. AEBSF, an inhibitor of OASIS, suppressed kidney fibrosis at day 7 after UUO. Moreover, kidney fibrosis was ameliorated in OASIS KO mice compared with WT mice, accompanied by decreased proliferation of myofibroblasts. To explore the downstream of OASIS, DNA microarray was performed using myofibroblasts from OASIS KO mice. Interestingly, it was found that bone marrow stromal antigen 2 (BST2) was a candidate downstream gene of OASIS. Anti-BST2 antibody treatment attenuated UUO-induced kidney fibrosis.Conclusion OASIS contributes to the develop of kidney fibrosis by promoting the proliferation of myofibroblasts, in part, through increased BST2 expression. OASIS could be a therapeutic target against kidney fibrosis.
Regorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was ...achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years.
A 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression.
To the best of our knowledge, this is the longest treatment with regorafenib without tumor progression ever reported. A reduced dosage of regorafenib at induction may ameliorate the cutaneous and hepatic toxicity associated with its use.
A 57-year-old woman with ovarian cancer underwent sigmoid colostomy because of rectovaginal fistula 4 years after primary surgery. Four days postoperatively, the discharge from the midline incision ...increased. Skin redness around the stoma and ulceration was found which lead to the diagnosis of pyoderma gangrenosum (PG). The necrosis spread widely around the wound, but the epithelization was finally restored by corticosteroid ointments on postoperative day 44. The characteristic ulcers were detected at the site of the central venous port on the left upper arm and the site of the peripheral intravenous feeding, and were both diagnosed as PG. PG is a rare disease which presents a characteristic ulcer as a cardinal symptom, and is often combined with inflammatory bowel diseases, autoimmune diseases and malignant tumors. It sometimes occurs around the stoma, but there have been no reports about consecutive PG occurrence at other sites such as the venous port and the peripheral intravenous puncture. We report this rare case with a review of the literature.
A 59-year-old woman had recurrences in the spleen and lung 10 years after radical excision of cecal cancer. After 27 months of treatment with 5-fluorouracil/Leucovorin, oxaliplatin, irinotecan, ...bevacizumab, and anti-EGFR antibodies, multiple bone metastases and a left adrenal metastasis developed, and the patient's performance status (PS) deteriorated to grade 3. Regorafenib was administered at 80 mg/day. The pain and appetite improved within 2 courses, and her PS improved from grade 3 to 2. Regorafenib was increased to 120 mg/day for the 2nd course, and the patient was treated for 5 months without severe adverse effects. Regorafenib is considered to be a salvage-line treatment only for patients in relatively good condition, because full-dose regorafenib treatment often leads to severe adverse effects. Dose escalation of regorafenib from the low initial dose of 80 mg/day may be a safe and effective way of providing an opportunity of this chemotherapy to patients with impaired PS.
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