Fibrosis is a response to injury (1), and is characterized by the excessive accumulation of connective tissue, which is associated with organ damage (2). It occurs in various organs, especially in the liver and kidney. The prevalence of liver fibrosis is estimated at 25% of the general population, while renal fibrosis affects about 17% of individuals (3). Fibrosis can be caused by various factors, such as infection, chemical exposure, and autoimmune reactions (2). The key features of fibrosis are fibroblast activation and ECM deposition, which lead to scarring of tissue, and disrupt normal organ function (2, 4). Fibrosis is tightly regulated by various pathways, which include TGF-β, NF-κB, Wnt, and Notch (5-7). Despite the improved understanding of the molecular mechanisms underlying fibrosis, effective therapeutic strategies are still limited (8, 9).
Recent advances in sequencing technology have revealed the cellular and molecular processes of fibrosis that are determined by epigenetic regulation. Over the past few years, numerous ncRNAs have emerged as pivotal players in fibrosis development and regulation at multiple cellular levels. Therefore, the functional role of ncRNAs as biomarkers for the diagnosis and targeted treatment of fibrosis has been proposed (10-12). lncRNAs have been implicated in liver and kidney fibrosis progression, highlighting their critical role in fibrogenesis (13-20).
LncRNAs are RNA transcripts that are similar to mRNAs, but do not encode proteins, and have a length of over 200 nucleotides (21-23). They can act as key regulators of gene expression and signaling pathways, and play fundamental roles in physiological processes and pathological conditions, including proliferation, differentiation, fibrosis, and malignancy (21, 22, 24). lncRNAs exert regulatory control over gene expression through multifaceted mechanisms. These include the ability to interact with DNA, RNA, and proteins, therby modulating chromatin structure, regulating mRNA turnover, and influencing mRNA translation. Additionally, lncRNAs engage with chromatin modifiers to either activate or suppress specific target genes. Moreover, certain lncRNAs participate in post-transcriptional regulation by sequestering proteins through their binding to RNA sequences or structures, leading to the formation of lncRNA-protein complexes. This process ultimately contributes to modified mRNA decay and modulation of signaling pathway (22).
In fibrosis models, lncRNAs modulate the expression of fibrosis-related genes or proteins through various regulatory mechanisms. For example, lncRNAs can stimulate the epigenetic activation or repression of fibrosis genes, interact with other miRNAs, or regulate mRNA stability, leading to either increased or decreased mRNA expression. Additionally, lncRNAs can regulate target protein translocation, phosphorylation, and ubiquitination (16-20, 22-25).
Thus, lncRNAs can exert both promoting and inhibitory effects on signaling pathways implicated in fibrosis through their regulation of gene expression. The significance of lncRNAs in fibrosis has been increasing, and recent studies have focused on developing fibrosis treatments targeting lncRNAs (18, 19, 26, 27). In this review, we provide an overview of our current understanding of the biological function of lncRNAs in liver and kidney fibrosis, and discuss the prospect of epigenetic therapy using lncRNAs for fibrosis treatment.
In both the liver and the kidney, the fibrosis process can lead to organ dysfunction, which is characterized by the extensive deposition of scar tissue and impaired organ function. Nevertheless, there exist fundamental differences in the fibrosis process between these two organs that warrant further investigation.
In the liver, fibrosis often results from chronic liver injury of inflammation, such as that caused by viral hepatitis, alcohol abuse, or non-alcoholic steatohepatitis (NASH) (28-32). Hepatic stellate cells (HSCs) are the main cells responsible for producing and depositing excess ECM proteins in the liver, leading to the formation of scar tissue. HSCs are activated by various signals, such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF), which are released in response to liver injury or inflammation. Once activated, HSCs undergo a transformation from quiescent cells to proliferative and fibrogenic cells, which produce and secrete ECM proteins (33).
In the kidney, fibrosis can occur as a result of various diseases, such as diabetic nephropathy (DN), glomerulonephritis, and chronic kidney disease (CKD). The fibrosis process in the kidney is initiated by injury to the glomerular or tubular cells, which leads to the activation of myofibroblasts, the cells responsible for producing and depositing excess ECM proteins in the kidney. Myofibroblasts are derived from various sources, including resident fibroblasts, pericytes, and epithelial cells that undergo a process of epithelial-to-mesenchymal transition (EMT). The production and deposition of excess ECM proteins by myofibroblasts lead to the formation of scar tissue, which can impair kidney function (33-38). Although drivers of liver/kidney damage might affect organs in an organ-specific manner, the fibrogenesis and associated cascades are conserved between organs (39).
Here, we summarize the lncRNAs that are associated with fibrosis in the liver and kidney, and categorize them into those that enhance or protect fibrosis in each tissue.
Despite the differences in the fibrosis process between the liver and kidney, there are several lncRNAs that are commonly promoting or repressing fibrosis in both organs (Fig. 1, Table 1). However, it is noteworthy that the precise functions of these lncRNAs can differ significantly between each tissue, highlighting the need for a tissue-specific approach to elucidate their mechanisms of action.
Dysregulated lncRNAs induce liver fibrosis through various biological mechanisms, including the regulation of fibrogenic proteins and miRNAs. First, there is lncRNA promoting transcription of fibrotic genes via regulating transcription repressor. LncRNA H19 is predominantly expressed in tissues during embryo development, but becomes downregulated after birth (40). Therefore, the re-expression of H19 has been implicated in various human diseases, and its dysregulation is considered as pathogenic factor (40). H19 was upregulated in the fibrotic liver of CCl4-induced mouse. Increased H19 in human cholestatic liver fibrosis was inversely correlated with EpCAM expression by downstream target of ZEB1. ZEB1 down-regulates EpCAM transcription by the binding of EpCAM promoter, and H19 represses ZEB1 activation (Fig. 1A). Note that the increase of H19 activates EpCAM expression by interacting with ZEB1, and leads to biliary hyperplasia (41).
In addition to this, lncRNA exerts as fibrogenic factor by regulating nuclear translocation of transcription factor induced by TGFβ. Liver fibrosis associated lncRNA1 (lnc-LFAR1) is identified as a liver enriched lncRNA in fibrotic mouse liver. lnc-LFAR1 expression raised CCl4 and bile duct ligation (BDL)-induced hepatic fibrosis in mice. lnc-LFAR1 directly binds to Smad2/3, promotes the transcription of Notch2/3, and activates the Notch signaling pathway (Fig. 1B). Therefore, lnc-LFAR1 promotes liver fibrosis and HSC activation (42).
Among the fibrogenesis regulated by lncRNAs, miRNA-mediated mechanism studies have been the most reported. Research of lncRNA that promotes liver fibrosis include: lnc-C18orf26-1 was up-regulated in TGF-β1 activated LX-2 cells, and suppressed miR-663a expression which in turn repressed the proliferation and activation of HSCs by silencing the TGF-β/Smad signaling pathway (Fig. 1C) (43). Similarly, lncRNA MBI-52, also known as SCARNA10, was increased in CCl4-induced mouse liver fibrosis and repressed miR-466g expression (Fig. 1C), leading to the reduction of SMAD4 expression and promoting liver fibrosis through the miR466g/SMAD4 axis (44, 45). Small nucleolar RNA host gene 7 (SNHG7), involved in the progression of multiple cancers (46), functions as a miRNA sponge and interacts with proteins, influencing cellular processes (47-49). However, it has also been observed to be highly expressed in human fibrotic liver tissues of cirrhosis, and showed a meaningful diagnostic value for liver fibrosis. Mechanistically, SNHG7 targeted and inhibited miR-378a-3p expression to activate Wnt/β-catenin pathway, resulting in HSC activation in liver fibrosis (Fig. 1C) (50). In addition, homeobox transcript antisense RNA (HOTAIR) was also found to be dysregulated in fibrotic tissues as well as various types of cancers. Various studies provide evidence for the biological function of HOTAIR in regulating gene expression and chromatin dynamics (51). HOTAIR was highly expressed in HSCs during liver fibrosis, and knockdown of HOTAIR let to an increase in miR-29b expression (Fig. 1C) and inhibition of DNMT3b (52). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as one of the highly conserved lncRNAs, plays its molecular role in various pathological processes via regulating transcription, mRNA splicing, and acting as a miRNA sponge (53-55). In liver fibrosis model, the expression of MALAT1 was associated with the fibrosis stages and severity in human fibrotic liver. MALAT1 levels in the patients were higher than in the healthy group, whereas miR-181-5p levels were reduced in patients with hepatic fibrosis (Fig. 1C) (56). Lastly, Nuclear enriched abundant transcript 1 (NEAT1) which is widely expressed in mammalian cell types, and plays critical roles in diverse pathophysiological processes (57) has been reported that its upregulation regulates multiple gene expression through acting as miRNA sponge in liver fibrosis (58, 59). Exosomes derived from lipopolysaccharide (LPS)-treated THP-1 macrophages show elevated levels of NEAT1 (60). It has been reported that LPS-stimulated THP-macrophages contribute to the progression of hepatic fibrosis by promoting HSCs activation (61). Macrophage exosomal NEAT1 promotes HSC activation by sponging miR-342 (Fig. 1C), which leads to the activation of Sp1/TGF-β1/Smad signaling pathway to induce hepatic fibrosis progression (60).
Some lncRNAs acting as sponges for miRNAs also contribute to inhibiting liver fibrosis. The relevant evidences are as follows. Growth arrest-specific transcript 5 (GAS5) is widely expressed in various human tissues, and has been identified as playing a significant role in the pathogenesis of several fibrotic diseases, as well as in regulating growth and apoptosis (62-66). In Carbon tetrachloride (CCl4)-induced hepatic fibrosis model, down-regulated GAS5 increases miR-23a expression via direct interaction to miR-23a (Fig. 1C). MiR-23a inhibits PTEN expression, which results in activating PI3K/Akt/mTOR/Snail signaling pathway to increase collagen I and α-SMA expression. Consequently, GAS5 can be used as a sponge for miR-23a to suppress miR-23a expression competitively, relieving the liver fibrosis (62). Also, significant reduction of MEG3 was demonstrated in the serum of liver fibrosis patients. MEG3 competed endogenously with miR-145 to modulate PPARγ (Fig. 1C). Overexpression of PPARγ downregulated the proliferation and activation markers in HSCs. Through this mechanism, MEG3 overexpression inhibited HSC proliferation and COL1A1 and α-SMA expression (67).
Compiling evidence demonstrated that lncRNA regulates target protein expression through regulating post-translational modification, such as ubiquitination. LncRNA that regulates the fibrosis mechanism by regulating protein ubiquitination includes lncRNA-ARAP1 antisense RNAs (ARAP1-AS2). This lncRNA has been identified as the antisense of the ARAP1. In DN mice model, ARAP1-AS2 was increased and interacted with ARAP1, which maintains EGFR activation via the reduction of EGFR ubiquitination. Through this mechanism, ARAP1-AS2 could regulate fibrosis via the activation of EGFR/TGF-β/Smad3 pathway by interacting with ARAP1 (Fig. 1D) (68).
LncRNAs that function as positive regulator via regulating miRNA expression has been elucidated in kidney fibrosis. In kidney fibrosis, H19 promotes kidney fibrogenesis via regulating miRNA. The H19 was found to be increased in a renal fibrosis mouse model induced by DN. Up-regulated H19 was associated with the suppression of miR-29a (Fig. 1F) and promoted the expression of Endothelial-mesenchymal transition (EndMT)-associated gene FSP-1. Knockdown of H19 altered miR-29a levels, inactivating the TGF-β/Smad pathway, leading to suppression of EndMT and kidney fibrosis (69). In the renal interstitial fibrosis (RIF) rat model, HOTAIR is increased, which downregulates miR-124 and activates the Notch1/Jagged1 signaling pathway (Fig. 1F). Silencing of HOTAIR upregulated miR-124, and inhibited EMT and migration in rat kidney interstitial fibroblast cells. Consequently, inhibition of HOTAIR reduced the expression of activated Notch1, and alleviated RIF (70). The KCNQ1OT1 was also increased in renal fibrosis mouse model induced by UUO, suggesting KCNQ1OT1 is involved in the progression of renal fibrosis. In kidney fibrosis, KCNQ1OT1 promotes kidney fibrogenesis via its direct target miRNA, miR-124-3p (Fig. 1F). Down-regulation of KCNQ1OT1 inhibited cell proliferation and decreased fibronectin and α-SMA through miR-124-3p up-regulation. KCNQ1OT1 knockdown represents an anti-fibrotic effect for renal fibrosis treatment (71). In addition, MALAT1 has been reported that it was upregulated, and interacted with miR-2355-3p in DN rat model (Fig. 1F). miR-2355-3p was downregulated in DN rats and high glucose treated human renal tubular cells. MALAT1 promoted the expression of IL6ST via regulating miR-2355-3p, and upregulated IL6ST activated the STAT3/NF-κB profibrogenic axis, aggravating renal fibrosis in rat (72). NEAT1 was also identified in kidney fibrosis model as well as liver fibrosis model. Increased NEAT1 in UUO-induced renal fibrosis mouse negatively regulates miR-129 (Fig. 1F) and miR-129 bound to collagen I. Silencing of NEAT1 alleviated histological damage
Phosphorylation of protein is considered as major switch for regulating various pathogenic pathways. In fibrosis, TGFβ-induced phosphorylation of Smad2/3 increases expression of fibrotic genes by allowing the Smad2/3 to translocate into the nucleus. There is lncRNA involved in phosphorylation of Smad2/3 in kidney fibrogenesis. A kidney-enriched TGF-β/Smad3-interacting lncRNA, which called lnc-TSI, that was inversely correlated with fibrosis and renal failure in human IgA nephropathy. Mechanistically, lnc-TSI interacted with the MS2 domain of Smad3 and inhibited Smad3 phosphorylation. lnc-TSI could inhibit the profibrotic gene expression by blocking the interaction of Smad3 with TGFBR1 (73). Therefore, lnc-TSI inhibits kidney fibrosis via negatively regulating the TGF-β/Smad3 pathway (Fig. 1E).
LncRNAs could serve as anti-fibrotic factors via regulating miRNA expression in kidney fibrogenesis. GAS5 was found to be decreased in unilateral ureteral obstructive (UUO) nephropathy mice known as kidney fibrosis model. GAS5 interacted with miR-142-5p to regulate fibrosis via the TGF-β1/Smad3 pathway (Fig. 1F). Depletion of GAS5 induced mouse tubular epithelial cell apoptosis through the Smad3 pathway. The renal-protective role of GAS5 via the Smad/miR-142-5p axis regulated ECM formation and cell apoptosis (64). In UUO-induced renal fibrosis rat, lncRNA4474 was downregulated. lncRNA4474 overexpression increased the expression of HNF-1β by reducing miR-615 expression (Fig. 1F), and inactivated the Wnt signaling pathway (74).
A number of lncRNAs, including H19, KCNQ1OT1, MALAT1, NEAT1, and GAS5, have been found to be dysregulated in fibrogenesis of various organs. For instance, increased expression of H19 and decrease expression of miR-29a/b-3p have been associated with enhanced proliferation and ECM synthesis in cardiac fibroblasts (75). Additionally, in a bleomycin-induced lung fibrosis model, upregulation of H19 acted as a miR-196a sponge, resulting in increased expression of COL1A1 (76).
In hyperglycemia-induced cardiac fibroblasts, KCNQ1OT1 was upregulated and its knockdown alleviated pyroptosis and fibrosis through the TGF-β1 pathway. In an acute lung injury (ALI) mouse model, repression of KCNQ1OT1 relieved pathological damage, fibrosis, and inflammation (77).
Similarly, lncRNA MALAT1 was noted to upregulate in angiotensin II (AngII)-treated cardiac fibroblasts. The knockdown of MALAT1 alleviated proliferation, collagen production and α-SMA expression in cardiac fibroblasts. Moreover, lncRNA MALAT1 is increased in silica-treated human bronchial epithelial cells and appears to affect the EMT process in silica-induced pulmonary fibrosis through miR-503/PI3K signaling pathway (78).
LncRNA NEAT1 was found to be elevated in heart failure patients and TGF-β1 treated cardiac fibroblasts (79). Notably, NEAT1’s increase in TGF-β1-treated bronchial epithelial cells suggests a potential association with pulmonary fibrosis, with its down-regulation seemingly reducing the migratory ability and collagen production of epithelial cells (80).
Furthermore, GAS5 has been identified as a potential inhibitor of fibrogenesis in the heart and lung. MeCP2 was highly expressed in cardiac fibrosis tissue and lncRNA GAS5 was decreased in cardiac fibroblast activation by TGF-β1. Overexpression of GAS5 inhibited cardiac fibroblasts activation by interacting with the Smad3. These results could provide valuable insights for developing cardiac fibrosis treatment strategies (81). Moreover, GAS5 expression decreased in idiopathic pulmonary fibrosis (IPF) patients and their overexpression reduced lung fibrosis in mice by regulating PDGFRα/β expression (82). In conclusion, these commonly dysregulated lncRNAs might serve as potential targets for preventing organ fibrosis (83).
LncRNAs, including GAS5, MEG3, H19, and MALAT1, have been implicated in the pathogenesis of fibrosis and exhibit dysregulation in liver and kidney fibrosis models. The identification of these lncRNAs has provided significant evidence for the initiation of therapeutic validation studies. To explore the therapeutic potential of these lncRNAs,
GAS5 was poorly expressed in kidney and liver fibrosis tissues, demonstrating that decreased expression of GAS5 might be a key player affecting fibrosis progression. Since the GAS5 was decreased in DN kidney fibrosis model (Fig. 2A), lentiviruses expressing GAS5 were injected in DN rat model to validate the therapeutic effect of GAS5 overexpression on the progression of kidney fibrosis. The GAS5 repressed MMP9 expression by interacting with EZH2 to MMP9 promoter, and elevating H3K27me3 enrichment. The GAS5 restoration reduced the expression of fibrosis markers and area of renal interstitial fibrosis (RIF)
MEG3 was downregulated in liver fibrosis patients and mice of liver fibrosis induced by CCl4. MEG3 interacted with SMO protein, and inhibited Hedgehog pathway. Overexpression of MEG3 in CCl4 mice using adenovirus reduced collagen accumulation and hydroxyproline level, suggesting the MEG3 as suppressor of liver fibrosis
H19 up-regulated lncRNA in bile duct ligation (BDL)-induced liver fibrosis mouse model, and H19-defeciency in BDL-induced cholestasis mice prevented liver fibrosis (Fig. 2C) (41). The anti-fibrotic effect of H19 silencing was also verified in kidney fibrosis model. H19 shRNA treatment to streptozotocin (STZ)-induced diabetic mice inactivated the TGF-β/SMAD3 pathway, and down-regulated EndMT. Inhibition of H19 in diabetic mice significantly attenuated kidney fibrosis, and recovered normal kidney structure (69).
MALAT1 was increased in fibrotic kidneys of STZ-induced diabetic rat, and knockdown of MALAT1 reduced fibrosis markers, and might improve renal fibrosis in this model (Fig. 2D) (72). In line with this evidence, the therapeutic effect of MALAT1 inhibition in fibrotic liver tissues was also validated. MALAT1 was found to be increased in CCl4-induced liver fibrosis, and mediated Rac1 expression by binding with miR-101b. Knockdown of MALAT1 using adenoviral vectors alleviated collagen accumulation
LncRNAs are expressed in various clinical samples and exhibit disease-specific patterns, making them valuable as diagnostic, prognostic, and therapeutic targets. Recently, several strategies have been developed to target lncRNAs in disease models. One such strategy involves the use of exosomes, which are extracellular vesicles containing protein, mRNA, and non-coding RNA cargoes that mediate intercellular communication (88). There is evidence to support the therapeutic potential of exosomes in fibrogenesis. For example, exosomes loaded with microRNA-122 can repress the activation of hepatic stellate cells (HSCs) and attenuate liver fibrosis (89). Exosomes derived from mesenchymal stem cells (MSCs) have also been shown to alleviate liver fibrosis by inhibiting HSC activation (90).
Apart from exosomes, antisense oligonucleotides (ASOs), including GapmeR, have emerged as a promising tool to regulate lncRNA expression, and their therapeutic effects have been validated.
The identification of serum biomarkers holds great significance in developing non-invasive methods for patient diagnosis and prognosis. lncRNAs exhibit stable expression in serum, making them potential prognostic markers for various diseases, including fibrotic conditions.
In chronic hepatitis B (CHB) patients, serum levels of lncRNA-MEG3 were found to be decreased compared to healthy controls, and its expression negatively correlated with the degree of liver fibrosis (93). Similarly, levels of serum exosomal H19 were increased in patients with biliary atresia (BA), a condition characterized by cholestasis and liver fibrosis. Furthermore, H19 expression was higher in BA patients with severe fibrosis compared to those with mild fibrosis (94). These findings demonstrate the potential of serum-based lncRNA biomarkers not only in liver fibrosis but also in kidney fibrosis. In the context of fibrotic kidney diseases, increased expression of circulating lncRNA-ANRIL has been associated with the progression of diabetic kidney disease (DKD) patients. This suggests that lncRNA-ANRIL could serve as a risk factor for DKD (95). Therefore, dysregulated lncRNAs in serum have the potential to serve as biomarkers for predicting disease progression in fibrotic liver and kidney conditions.
As fibrosis is a common life-threatening phenomenon in various diseases, pathogenic mechanisms and potential therapeutic targets to alleviate fibrosis have been proposed. lncRNAs were recently recognized as pathogenic factors of liver and kidney fibrosis; aberrant lncRNAs expression promoted the fibrosis mechanism, and restoration of these lncRNAs showed therapeutic effects in fibrosis models. Interestingly, along with the increasing number of reports of correlation between lncRNAs and fibrosis, studies that show links between anti-fibrotic drugs and lncRNAs are also being reported. Some preclinical and approved drugs for treating liver and kidney fibrosis regulate lncRNA expression to alleviate fibrosis. Rosiglitazone, known as a PPAR-γ agonist, protects kidneys from the damage of DN via altering lncRNA expression (96). In addition, dioscin, proven to be effective in treating liver fibrosis, attenuates fibrosis in cardiac dysfunction model, via regulating lncRNA expression (97). This evidence supports that the development of therapies targeting the lncRNAs could be effective for fibrosis treatment. Therefore, if the clinically meaningful lncRNAs involved in fibrogenesis are elucidated, and drug delivery systems that can stably regulate these lncRNAs are developed, it will be possible in the future to overcome liver and kidney diseases by alleviating fibrosis.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2022M3A9B6082667).
The authors have no conflicting interests.
lncRNAs involved in liver and kidney fibrosis by signaling pathways
|Role in fibrosis||lncRNA||Disease model||Binding partner (RBPs, miRNAs)||Target||Possible pathway||References|
|Promoting in liver||H19||BDL-induced mouse liver fibrosis model||Interacts with ZEB1||Down-regulation of EPCAM||etc.||(41)|
|lnc-LFAR1||Activated mouse HSCs||Interacts with Smad2/3||Up-regulation of transcription of TGFβ, Smad2/3, Notch2/3||Notch pathway||(42)|
|CCl4 and BDL-induced mouse liver fibrosis model|
|lnc-C18orf26-1||TGF-β1-activated LX-2 human cells||Downregulates miR-663a||Up-regulation of α-SMA and COL1A2 Renal fibrosis in STZ-induced DN rats||TGF-β pathway||(43)|
|MBI-52||CCl4-induced mouse liver fibrosis model||Downregulates miR-466g||Up-regulation of SMAD4||TGF-β pathway||(44, 45)|
|SNHG7||LX-2 human cells and primary mouse HSCs||Downregulates miR-378a-3p||Up-regulation of DVL2||Wnt pathway||(50)|
|Human fibrotic livers|
|CCl4-induced mouse liver fibrosis model|
|HOTAIR||Chronic HBV-infected patients||Downregulates miR-29b||Restoration of DNMT3b||etc.||(52)|
|CCl4-induced mouse liver fibrosis model||Enhancement of PTEN methylation|
|MALAT1||TGF-β1 or LPS-activated LX-2 human cells||Downregulates miR-181-5p||Activating TLR4/NF-κB signaling||etc.||(56)|
|Liver fibrosis or chronic HBV associated liver fibrosis patients|
|NEAT1||LX-2 human cells and primary mouse HSCs||Downregulates miR-342||Up-regulation of Sp1||TGF-β pathway||(60)|
|CCl4-induced rat liver fibrosis model|
|Inhibiting in liver||GAS5||CCl4-induced rat liver fibrosis model||Downregulates miR-23a||Up-regulation of PTEN||etc.||(62)|
|MEG3||TGF-β1-activated LX-2 human cells||Downregulates miR-145||Up-regulation of PPAR-γ||etc.||(67)|
|Patient with liver fibrosis|
|Promoting in kidney||ARAP1-AS2||HG-induced human tubular epithelial cell line HK-2db/db diabetic mice||Interacts with ARAP1||Reduction of EGFR ubiquitination||TGF-β pathway||(68)|
|H19||Human dermal microvascular endothelial cells (HMVECs)||Downregulates miR-29a||Up-regulation of FSP-1||TGF-β pathway||(69)|
|Renal fibrosis in STZ-induced DN rats|
|HOTAIR||TGF-β1-activated normal rat kidney interstitial fibroblast (NRK-49F)||Downregulates miR-124||Up-regulation of Notch1||Notch pathway||(70)|
|Renal fibrosis in unilateral ureteral obstruction (UUO) rats|
|KCNQ1OT1||TGF-β1-activated human tubular epithelial cell line HK-2||Downregulates miR-124-3p||Up-regulation of α-SMA and fibronectin||etc.||(71)|
|Renal fibrosis in UUO mice|
|MALAT1||Renal fibrosis in STZ-induced DN rats||Downregulates miR-2355-3p||Up-regulation of IL6ST||etc.||(72)|
|NEAT1||TGF-β1-activated human tubular epithelial cell lines HK-2 and HKC-8||Downregulates miR-129||Up-regulation of collagen I||etc.||(59)|
|Renal fibrosis in UUO mice|
|Inhibiting in kidney||lnc-TSI||Human IgA nephropathy||Interacts with Smad3||Inhibition of binding with TGFBR1||TGF-β pathway||(73)|
|Renal fibrosis in UUO mice|
|GAS5||Renal fibrosis in UUO mice||Downregulates miR-142-5p||Up-regulation of Smad3||TGF-β pathway||(64)|
|lncRNA4474||TGF-β1-activated human tubular epithelial cell line HK-2||Downregulates miR-615||Up-regulation of HNF-1β||Wnt pathway||(74)|
|Renal fibrosis in UUO rats|
RBPs, RNA binding proteins; CCl4, Carbon tetrachloride; UUO, Unilateral ureteral obstruction; BDL, Bile duct ligation; HSCs, Hepatic stellate cells; STZ, Streptozocin; DN, Diabetic nephropathy; HBV, Hepatitis B virus; LPS, Lipopolysaccharides.