Effective Therapy For Renal Fibrosis: Pharmacological Inhibition Of STAT6 With AS1517499
Mar 24, 2022
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PART Ⅱ： Pharmacological Inhibition of STAT6 Ameliorates Myeloid Fibroblast Activation and Alternative Macrophage Polarization in Renal Fibrosis
Baihai Jiao, Changlong An, Melanie Tran, Hao Du, Penghua Wang, Dong Zhou and Yanlin Wang
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 the 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 the AS1517499 treatment. Mice treated with AS1517499 accumulated fewer myeloid fibroblasts and myofibroblasts in the kidney with a 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 the 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.
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DISCUSSION
Renal fibrosis is a key pathological feature of chronic kidney disease. At present, there are no effective treatments or specific drugs for preventing and/or reversing renal fibrosis progression. Studies have demonstrated that a major source of myofibroblasts originates from bone marrow-derived fibroblasts, which is derived from monocyte subpopulations through the differentiation of monocytes into fibroblasts(9, 23,30,31). However, the molecular mechanisms underlying monocytes-to-fibroblast transition in the injured kidney are not fully elucidated. In the present study, we examined the effect of a STAT6-specific inhibitor, AS1517499, on monocyte-to-fibroblast transition, M2 macrophage polarization, and development of renal fibrosis in two murine models of chronic kidney disease induced by ureteral obstruction or folic acid. Our results show that treatment with AS1517499 in mice with obstructive nephropathy or FA nephropathy suppresses myeloid fibroblast accumulation, decreases M2 macrophage polarization and myofibroblast transformation, reduces ECM protein production and collagen deposition in the kidney, and prevents kidney dysfunction.
We have shown that the IL4Ro/JAK3/STAT6 signaling pathway plays an important role in the activation of myeloid fibroblast and the development of renal fibrosis (15). Genetic disruption of IL4Rα, pharmacological inhibition of JAK3, or genetic deletion of STAT6 reduces myeloid fibroblast accumulation and activation in the kidney in response to obstructive injury or folic acid injury(15,16).AS1517499 is a potent and selective STAT6 inhibitor with an IC50 of 21 nM (21). Chiba and colleagues report that AS1517499 inhibits antigen-induced hyperresponsiveness in a murine model of asthma(22). In the present study, we examine the effect of pharmacological inhibition of STAT6 with AS1517499 on myeloid fibroblast activation in experimental models of renal fibrosis induced by ureteral obstruction or folic acid. Our results reveal that STAT6 is phosphorylated in the kidney in response to obstructive injury or folic acid injury. The level of STAT6 phosphorylation in the kidney is markedly inhibited by AS1517499 administration. These data indicate that AS1517499 inhibits STAT6 activation in the kidney with injury. Of note, the total STAT6 levels in the kidney are increased following ureteral obstruction or folic acid administration, which is somewhat reduced after AS1517499 treatment. This may be related to STAT6 protein stability/degradation or decreased expression of STAT6 as a consequence of negative feedback regulation caused by the inactivation of STAT6 signaling. Further studies are needed to elucidate the exact mechanisms. We observed that AS1517499 treatment inhibits myeloid fibroblast accumulation and activation in the kidney with injury. These results support an important role of STAT6 in the activation of myeloid fibroblasts in the kidney.
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Th2 cytokines IL-4 and IL-13 stimulate STAT6 phosphorylation, which is involved in M2 macrophage polarization(15). M2 macrophages are characterized by expressing Argl, MRCl, Fizzl, CCL17 (32). M2 macrophages have been reported to promote tissue fibrosis(33-35). However, how M2 macrophages promote tissue fibrosis is not clearly understood. We have previously demonstrated that myeloid fibroblasts are derived from monocytes through M2 macrophage polarization(15,24). Recently, Binnemars-Postma and colleagues report that inhibition of STAT6 with AS1517499 attenuates tumor-associated macrophages into M2 phenotypes and reduces tumor growth and metastasis(36). In the present study, we show that treatment with AS1517499 inhibits the number of CD206 and PDGFR-β dual positive cells in the injured kidney and reduces the mRNA expression levels of M2 macrophage markers, Argl, MRCl, Fizzl, CCL17. These data indicate that STAT6 inhibitor A1517499 suppresses monocyte-to-fibroblast transition and M2 macrophage polarization in the injured kidney during the development of renal fibrosis.
Renal fibrosis is characterized by the production and deposition of ECM proteins leading to the destruction of renal parenchyma and loss of kidney function(2).In the present study, we have shown that inhibition of STAT6 with AS1517499 reduces the production of ECM proteins -fibronectin and collagen I as well as collagen deposition in the kidney in two experimental models of obstructive nephropathy and folic acid nephropathy. Furthermore, pharmacological inhibition of STAT6 with AS1517499 protects the kidney from folic acid-induced kidney dysfunction. These results indicate that AS1517499 can inhibit the development of kidney fibrosis and dysfunction.
In summary, our findings indicate that STAT6 is activated in injured kidneys, leading to the accumulation and activation of myeloid fibroblasts, M2 macrophage polarization, and the development of kidney fibrosis and dysfunction. Pharmacological inhibition of STAT6 with AS1517499 suppresses myeloid fibroblasts accumulation and activation, reduces M2 macrophage polarization, decreases ECM protein production, and attenuates the development of kidney fibrosis and dysfunction. These results indicate that targeting STAT6 with AS1517499 is a promising therapeutic approach for the treatment of chronic kidney disease.
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