Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis
A hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effec...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.735014/full |
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| author | Baihai Jiao Changlong An Melanie Tran Hao Du Penghua Wang Dong Zhou Yanlin Wang Yanlin Wang Yanlin Wang Yanlin Wang |
| author_facet | Baihai Jiao Changlong An Melanie Tran Hao Du Penghua Wang Dong Zhou Yanlin Wang Yanlin Wang Yanlin Wang Yanlin Wang |
| author_sort | Baihai Jiao |
| collection | DOAJ |
| description | A hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effect of a selective STAT6 inhibitor, AS1517499, on myeloid fibroblast activation, macrophage polarization, and development of renal fibrosis in two experimental murine models. To investigate the effect of STAT6 inhibition on myeloid fibroblast activation, macrophage polarization, and kidney fibrosis, wild-type mice were subjected to unilateral ureteral obstruction or folic acid administration and treated with AS1517499. Mice treated with vehicle were used as control. At the end of experiments, kidneys were harvested for analysis of myeloid fibroblast activation, macrophage polarization, and renal fibrosis and function. Unilateral ureteral obstruction or folic acid administration induced STAT6 activation in interstitial cells of the kidney, which was significantly abolished by AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with ureteral obstruction or folic acid nephropathy compared with vehicle-treated mice. Moreover, AS1517499 significantly suppressed M2 macrophage polarization in the injured kidney. Furthermore, AS1517499 markedly reduced the expression levels of extracellular matrix proteins, and development of kidney fibrosis and dysfunction. These findings suggest that AS1517499 inhibits STAT6 activation, suppresses myeloid fibroblast activation, reduces M2 macrophage polarization, attenuates extracellular matrix protein production, and preserves kidney function. Therefore, targeting STAT6 with AS1517499 is a novel therapeutic approach for chronic kidney disease. |
| first_indexed | 2024-12-21T20:41:31Z |
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| id | doaj.art-812b228935ae49288f683f61e4dbce97 |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T20:41:31Z |
| publishDate | 2021-08-01 |
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| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-812b228935ae49288f683f61e4dbce972022-12-21T18:50:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.735014735014Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal FibrosisBaihai Jiao0Changlong An1Melanie Tran2Hao Du3Penghua Wang4Dong Zhou5Yanlin Wang6Yanlin Wang7Yanlin Wang8Yanlin Wang9Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDepartment of Immunology, University of Connecticut School of Medicine, Farmington, CT, United StatesDivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDivision of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, United StatesDepartment of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, United StatesInstitute for Systems Genomics, University of Connecticut School of Medicine, Farmington, CT, United StatesRenal Section, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United StatesA hallmark of chronic kidney disease is renal fibrosis, which can result in progressive loss of kidney function. Currently, there is no effective therapy for renal fibrosis. Therefore, there is an urgent need to identify potential drug targets for renal fibrosis. In this study, we examined the effect of a selective STAT6 inhibitor, AS1517499, on myeloid fibroblast activation, macrophage polarization, and development of renal fibrosis in two experimental murine models. To investigate the effect of STAT6 inhibition on myeloid fibroblast activation, macrophage polarization, and kidney fibrosis, wild-type mice were subjected to unilateral ureteral obstruction or folic acid administration and treated with AS1517499. Mice treated with vehicle were used as control. At the end of experiments, kidneys were harvested for analysis of myeloid fibroblast activation, macrophage polarization, and renal fibrosis and function. Unilateral ureteral obstruction or folic acid administration induced STAT6 activation in interstitial cells of the kidney, which was significantly abolished by AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with ureteral obstruction or folic acid nephropathy compared with vehicle-treated mice. Moreover, AS1517499 significantly suppressed M2 macrophage polarization in the injured kidney. Furthermore, AS1517499 markedly reduced the expression levels of extracellular matrix proteins, and development of kidney fibrosis and dysfunction. These findings suggest that AS1517499 inhibits STAT6 activation, suppresses myeloid fibroblast activation, reduces M2 macrophage polarization, attenuates extracellular matrix protein production, and preserves kidney function. Therefore, targeting STAT6 with AS1517499 is a novel therapeutic approach for chronic kidney disease.https://www.frontiersin.org/articles/10.3389/fimmu.2021.735014/fullfibroblastsmacrophagesextracellular matrixrenal fibrosisSTAT6 |
| spellingShingle | Baihai Jiao Changlong An Melanie Tran Hao Du Penghua Wang Dong Zhou Yanlin Wang Yanlin Wang Yanlin Wang Yanlin Wang Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis Frontiers in Immunology fibroblasts macrophages extracellular matrix renal fibrosis STAT6 |
| title | Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis |
| title_full | Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis |
| title_fullStr | Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis |
| title_full_unstemmed | Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis |
| title_short | Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis |
| title_sort | pharmacological inhibition of stat6 ameliorates myeloid fibroblast activation and alternative macrophage polarization in renal fibrosis |
| topic | fibroblasts macrophages extracellular matrix renal fibrosis STAT6 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.735014/full |
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