LNA-anti-miR-150 alleviates renal interstitial fibrosis by reducing pro-inflammatory M1/M2 macrophage polarization

Abstract

Renal interstitial fibrosis (RIF) is a common pathological feature contributing to chronic injury and maladaptive repair following acute kidney injury. Currently, there is no effective therapy for RIF. We have reported that locked nuclear acid (LNA)-anti-miR-150 antagonizes pro-fibrotic pathways in human renal tubular cells by regulating the suppressor of cytokine signal 1 (SOCS1)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. In the present study, we aimed to clarify whether LNA-anti-miR-150 attenuates folic acid-induced RIF mice by regulating this pathway and by reducing pro-inflammatory M1/M2 macrophage polarization. We found that renal miR-150 was upregulated in folic acid-induced RIF mice at day 30 after injection. LNA-anti-miR-150 alleviated the degree of RIF, as shown by periodic acid–Schiff and Masson staining and by the expression of pro-fibrotic proteins, including alpha-smooth muscle actin and fibronectin. In RIF mice, SOCS1 was downregulated, and p-JAK1 and p-STAT1 were upregulated. LNA-anti-miR-150 reversed the changes in renal SOCS1, p-JAK1, and p-STAT1 expression. In addition, renal infiltration of total macrophages, pro-inflammatory M1 and M2 macrophages as well as their secreted cytokines were increased in RIF mice compared to control mice. Importantly, in folic acid-induced RIF mice, LNA-anti-miR-150 attenuated the renal infiltration of total macrophages and pro-inflammatory subsets, including M1 macrophages expressing CD11c and M2 macrophages expressing CD206. We conclude that the anti-renal fibrotic role of LNA-anti-miR-150 in folic acid-induced RIF mice may be mediated by reducing pro-inflammatory M1 and M2 macrophage polarization via the SOCS1/JAK1/STAT1 pathway.

Coinfection of Dermal Fibroblasts by Human Cytomegalovirus and Human Herpesvirus 6 Can Boost the Expression of Fibrosis-Associated MicroRNAs

“…Specifically, the pro-fibrotic miR-1, miR-19b; miR-122, miR-129, miR-150, miR-155, miR-192, miR-200b, miR-215, miR-216a, miR-32, miR-328, miR-375, miR-449b, miR-491, miR-661, and miR-7 were all more induced than in single-infected cells, showing values suggesting true synergism between the viruses rather than a mere additional effect. The pro-fibrotic action of the up-regulated miRNAs was well documented in several reports; miR-1 was reported as involved in increased fibrosis of the cartilage in acetabular dysplasia [ 43 ] and in liver fibrosis [ 44 ]; miR-19b-3p was associated with hypertrophic and fibrosis indexes in acute heart failure [ 45 ]; miR-122 has been related with fibrosis-induced cardiovascular remodeling [ 46 ] and, in this regard, it is intriguing that both HCMV and HHV-6A have been associated with cardiovascular diseases [ 25 , 47 , 48 , 49 ]; miR-150 was correlated with renal fibrosis and miR-150 antagonists can ameliorate the pro-fibrotic pathway in a mouse model [ 50 ]; miR-155 is essential in fibrosis and it is consistently up-regulated in fibrotic disorders [ 51 ]; miR-192 can promote fibrosis by transforming growth factor beta (TGF-β) activation, which is recognized as a major mediator of fibrosis [ 52 ], and its circulating levels are increased in patients with hypertrophic cardiomyopathy and diffuse myocardial fibrosis [ 53 ]; miR-200b was found to be up-regulated in fibrotic liver samples compared to non-fibrotic ones [ 54 ]; miR-216a accelerates fibrogenesis in cardiac fibroblasts [ 55 ]; miR-32 has been reported to mediate the glucose-induced hepatic fibrosis [ 56 ]); miR-328 was found to be up-regulated in cardiac fibrosis and shown to directly stimulate TGF-β1 signaling, promoting collagen production in cultured fibroblasts [ 57 ], although its pro-fibrotic role it is not so clear, since it has been also reported to prevent renal fibrogenesis [ 58 ]; miR-375 was recognized to promote cardiac fibrogenesis by accelerating the ferroptosis of cardiomyocytes through mediating glutathione peroxidase 4 (GPX4) [ 59 ]; the miR-449 family was detected to be up-regulated in cystic fibrosis [ 60 ] and in bleomycin-induced lung fibrosis [ 61 ] and able to activate TGF-β1 in nasopharyngeal carcinoma [ 62 ]; miR-491 is induced by TGF-β1 during renal fibrosis [ 63 ]; miR-661 has been recently shown to accelerate fibrosis by increasing fibroblast growth factor 2 (FGF2) [ 64 ]; miR-...…”

Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis

“…• Suppression of IL-6 expression by miR-410 [189] • Suppression of IL-17 and TGF-β expression by miR-125a-3p [192] • Suppression of IFN-I and JAK1 signaling by hsa-miR-127-3p [194] • Suppression of CSF-1 expression by miR-145 [195][196][197] • Decreased M1/M2 polarization (ratio) by locked nucleic acid-anti-miR-150, via SOCS1/JAK1/STAT1 signaling [206,207] IV Application of lncRNA and circRNA in the treatment of LN…”

Tolerogenic probiotics Lactobacillus delbrueckii and Lactobacillus rhamnosus promote anti‐inflammatory profile of macrophages‐derived monocytes of newly diagnosed patients with systemic lupus erythematosus

“…Furthermore, the results of a study on renal interstitial fibrosis (RIF) showed that reduction of pro-inflammatory M1/M2 macrophage polarization induced by locked nuclear acid (LNA)-anti-miR-150, may play a role in alleviating the RIF. 20 They also reported that the LNA-anti-miR-150 effects on macrophage polarization via SOCS1/Janus kinase/STAT1 pathway.…”

“…The significance of promoting the M2 macrophages and rebalancing the M1/M2 ratio in SLE pathogenesis have been proved by clinical studies as Zhou et al 19 reported that Mesenchymal stem cell (MSC) therapy ameliorated the kidney complications in lupus nephritis through affecting various immune cells namely reducing the infiltration of pro‐inflammatory macrophages beside increasing the anti‐inflammatory resident macrophages. Furthermore, the results of a study on renal interstitial fibrosis (RIF) showed that reduction of pro‐inflammatory M1/M2 macrophage polarization induced by locked nuclear acid (LNA)‐anti‐miR‐150, may play a role in alleviating the RIF 20 . They also reported that the LNA‐anti‐miR‐150 effects on macrophage polarization via SOCS1/Janus kinase/STAT1 pathway.…”