Table 3.
MicroRNAs Linked to Fibrosis
| MicroRNA | Effect | Organ | Predicted Target and Confirmation Level | Putative Role in Fibrosis | References |
|---|---|---|---|---|---|
| let-7d | Anti-fibrotic | Lung | Reporter gene assay (HMGA2) | ↓EMT | [48] |
| miR-107 | Anti-fibrotic | Kidney | - | ↓ Interstitial fibrosis in allograft transplant | [49] |
| miR-132 | Anti-fibrotic | Heart, liver | Target mRNA changes in mimic/silencing miRNA transfection (RAS-GTPase, MeCP2) | ↑angiogenesis and ↓myofibroblasts differentiation | [50, 51] |
| miR-133 | Anti-fibrotic | Heart | Reporter gene assay (CTGF, TGF-β1) | ↓ TGF-β signaling and ↓CTGF signaling | [52, 53] |
| miR-141 | Anti-fibrotic | Kidney | Reporter gene assay (TGF-β2) | ↓TGF-β and ↓TGF-β dependent EMT | [54] |
| miR-142-3p | Pro-fibrotic | Kidney | - | ↓Interstitial fibrosis in allograft transplant | [49] |
| miR-15b, miR-16 | Anti-fibrotic | Liver, lung | Reporter gene assay (Bcl-2) | ↑apoptosis | [55, 56] |
| miR-150 | Anti-fibrotic | Liver | Target protein changes in mimic/silencing miRNA transfection (c-myb) | ↓activation and proliferation in HSC | [57] |
| miR-155 | Pro-fibrotic | Lung, liver | Reporter gene assay (KGF-FGF-7); target protein changes in mimic/silencing miRNA transfection | ↓mesenchymal-epithelial cross-talk | [58, 59] |
| miR-17-92 cluster (miR-18a, 19a/b) | Anti-fibrotic | Liver, heart, lung | Target protein changes in mimic/silencing miRNA transfection (CTGF; CTGF and TSP-1) | ↓CTGF and ↓ TSP-1 | [48, 60, 61] |
| miR-192 | Pro-fibrotic | Kidney | Reporter gene assay (ZEB1/2) | ↑collagen synthesis and ↑EMT | [62, 63] |
| miR-194 (clustered with miR-215) | Anti-fibrotic | Liver | Target protein changes in mimic/silencing miRNA transfection (rac1) | ↓activation and ↓ proliferation in HSC | [57] |
| miR-199a/b | Pro-fibrotic | Heart, Liver | Reporter gene assay (Dyrk1); | ↑ECM synthesis via calcineurin/NFAT signaling | [64, 65] |
| miR-200 family (miR-200a/b) | Anti-fibrotic | Kidney, liver | Reporter gene assay (TGFβ2 for miR-200a, ZEB1/2 for miR-200b); target mRNA changes in mimic/silencing miRNA transfection | ↓TGF-β signaling and ↓ TGF-β -dependent EMT | [54, 59, 66] |
| miR-204 | Anti-fibrotic | Kidney | - | ↓Interstitial fibrosis in allograft transplant | [49] |
| miR-208 | Pro-fibrotic | Heart | Reporter gene assay (THRAP1 and myostatin) | ↓myocardial contractility and ↑fibrosis by de-repression of negative regulators of stress-response genes | [67] |
| miR-21 | Pro-fibrotic | Lung, heart, kidney | Reporter gene assay (Smad7 in lung); in vivo functional assay (Spry1 in heart); in vitro functional assay for Smad interactions | ↑TGF-β canonical (via Smad7 de-repression of Smad2/3) and non canonical signaling (via Spry1 de-repression of ERK/MAPK) | [68-70] |
| miR-211 | Anti-fibrotic | Kidney | - | ↓Interstitial fibrosis in allograft transplant | [49] |
| miR-215 | Pro-fibrotic | Kidney | Reporter gene assay (ZEB1/2) | ↑EMT | [63] |
| miR-216, miR-217 | Pro-fibrotic | Kidney | Reporter gene assay (PTEN) | ↑Akt signaling via PTEN de-repression | [71] |
| miR-23a (clustered with miR-27a) | Pro-fibrotic | Lung | Systems biology approach and real time PCR (ZEB1) | ↑EMT | [72] |
| miR-26a/b | Anti-fibrotic | Lung | Microarray | - | [48] |
| miR-27b, miR-27a | Pro-fibrotic | Liver | Reporter gene assay (RXR-α) | ↑lipid accumulation and ↑proliferation of HSC | [73] |
| miR-29a/b/c | Anti-fibrotic | SSc, heart, lung, kidney, liver | Reporter gene assays (different collagens, FBN1, ELN1, MMP2, ITGB1; target mRNA changes in mimic/silencing miRNA transfection | Directly ↓ECM synthesis | [47, 48, 59, 74-77] |
| miR-30c | Anti-fibrotic | Heart, lung | Reporter gene assay (CTGF) | ↓CTGF signaling | [48, 51] |
| miR-32 | Pro-fibrotic | Kidney | - | ↓Interstitial fibrosis in allograft transplant | [49] |
| miR-335 | Anti-fibrotic | Liver | Target mRNA changes in mimic/silencing miRNA transfection (TNC) | ↓HSC activation and migration | [78] |
| miR-338* | Pro-fibrotic | Lung | Reporter gene assay (LPA1) | ↑fibroblast proliferation | [79] |
| miR-34a | Pro-fibrotic | Liver | Reporter gene assay (ACSL1) | ↑lipids biosynthesis | [59, 80] |
| miR-377 (clustered with miR-382) | Pro-fibrotic | Kidney | Reporter gene assay (PAK1, SOD) | ↑fibronectin synthesis | [81] |
| miR-382 | Pro-fibrotic | Kidney | Reporter gene assay (SOD2) | ↑EMT mediated by ↓ protection against mitochondrial oxidative stress | [82] |
| miR-449a/b | Anti-fibrotic | Kidney | Target mRNA changes in mimic/silencing miRNA transfection (SERPINE1) | ↑ECM synthesis in hypoxic conditions via downregulation of miR-449 | [83] |
| miR-590 | Anti-fibrotic | Heart | Reporter gene assay (TGFβR2) | ↓TGF-β signaling | [53] |
EMT = epithelial-to-mesenchymal transition; HMGA2 = high mobility group AT-hook 2; RAS-GTPase = Rat sarcoma guanosine triphosphatase; MeCP2 = methylCpG binding protein 2; CTGF = connective tissue growth factor; TGF-β = transforming growth factor- β; Bcl-2 = B-cell lymphoma 2; HSC = hepatic stellate cell; c-myb = avian myeloblastosis proto-oncoprotein; KGF = keratinocytes growth factor; ZEB = zinc finger E-box-binding homebox; rac1 = Ras-related C3 botulinum toxin substrate 1; Dyrk1 = dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a; NFAT = nuclear factor of activated T-cells; βMHC = β myosin heavy chain; Smad = small mother against decapentaplegic; Spry1 = protein sprouty homolog 1; ERK = extracellular signal-regulated kinase; MAPK = mitogen activated protein kinase; PTEN = phosphatase and tensin homolog; Akt = non-specific serine/threonine-protein kinase; RXR-α = retinoid X receptor-α; FBN1 = fibrillin1; ELN1 = elastin1; MMP2 = metalloproteinase 2; ITGB1 = integrin β1; TNC = tenascin; LPA1 = lipophosphatidic acid; ACSL1 = Long-chain-fatty-acid-CoA ligase 1; PAK1 = p21 activated kinase 1; SOD = superoxide dismutase; TGF-β receptor 2 = transforming growth factor- β receptor type 2; TSP-1 = thrombospondin-1.