Long non-coding RNAs (lncRNAs) are a large, heterogeneous class of transcripts and key regulators of gene expression at both the transcriptional and post-transcriptional levels in different cellular contexts and biological processes. LncRNAs plays an important role in renal pathogenesis. Altered expression of lncRNAs has been increasingly closely related to the onset and development of many diseases due to their role in gene regulation processes at the transcriptional, post-transcriptional, translational, post-translational, and epigenetic levels. Therefore, increasing attention is being paid to their role as diagnostic and prognostic biomarkers and therapeutic targets in several human diseases. Regarding kidney diseases, there are numerous studies that have analyzed and demonstrated the role of lncRNAs mainly in diabetic nephropathy (DN) and acute kidney injury (AKI), and to a lesser extent in chronic kidney disease (CKD), focal segmental glomerulosclerosis (FSGs), and immunoglobulin A nephropathy (IgAN).
lncRNA | Tissue/Cells | Disease | Mechanism | |
---|---|---|---|---|
ARAP1-AS1 and ARAP1-AS2 | HK-2 | DN | Both enhance the mRNA expression of ARAP1, a member of the renin-angiotensin system [62,63] | Both enhance the mRNA expression of ARAP1, a member of the renin-angiotensin system [9][10] |
ENST-00000453774.1 | HK-2 | CKD | Reduces ECM-bound proteins fibronectin and collagen I [99] | Reduces ECM-bound proteins fibronectin and collagen I [46] |
Erbb4 –Immunoreactivity | TECs and elongated, fibroblast-like cells | CKD | Regulates the expression of collagen I, α–smooth muscle actin, and Smad7 [89] | Regulates the expression of collagen I, α–smooth muscle actin, and Smad7 [36] |
GAS5 | Kidney cells | CKD | Has anti-pyroptotic properties [100] | Has anti-pyroptotic properties [47] |
H19 | ECs, TECs | AKI due to renal I/R injury | Upregulates miR-30a-5p [81] | Upregulates miR-30a-5p [28] |
HK-2 | CKD | Affects TNF-α and IL-6 expression [93,95] | Affects TNF-α and IL-6 expression [40][42] | |
HOTAIR | PBMCs | IgAN | Possible involvement in the NGF signaling pathway and Toll-like receptor pathways [104] | Possible involvement in the NGF signaling pathway and Toll-like receptor pathways [51] |
HOXA-AS2 | HK-2 | AKI | Hinders the Wnt/β-catenin and NF-κB pathways [75] | Hinders the Wnt/β-catenin and NF-κB pathways [22] |
ICR | Renal Proximal Tubular Cells | IgAN | Is involved in the Akt/mTOR signaling pathway [108] | Is involved in the Akt/mTOR signaling pathway [55] |
LINC00667 | Renal Tubular Epithelial Cell | CKD | Regulates apoptosis, cell proliferation, autophagy, and EMT [97] | Regulates apoptosis, cell proliferation, autophagy, and EMT [44] |
lncRNA 9884 | HK-2 | AKI induced by nephrotoxic agents | Promotes the production of inflammatory cytokines via NF-κB [79] | Promotes the production of inflammatory cytokines via NF-κB [26] |
lncRN A6406 | PTEC | AKI | Modulates miR-687/PTEN signaling [76,77] | Modulates miR-687/PTEN signaling [23][24] |
lncRNA G21551 | Exosomes | IgAN | Regulates the expression of FCGR3B [105] | Regulates the expression of FCGR3B [52] |
lncRNA PTTG3P | Peripheral B cells | IgAN | Promotes B-cell growth, IL-1β, and IL-8 production by regulating miR-383 [106] | Promotes B-cell growth, IL-1β, and IL-8 production by regulating miR-383 [53] |
LOC105375913 | Renal tubular cells | FSGS | Increases the level of snail and tubulointerstitial fibrosis [101] | Increases the level of snail and tubulointerstitial fibrosis [48] |
LOC105374325 | Podocytes | FSGS | Increases the level of Bax and Bak genes and causes cell apoptosis [102] | Increases the level of Bax and Bak genes and causes cell apoptosis [49] |
MALAT1 | HK-2 | AKI | Activates NF-κB [70] | Activates NF-κB [17] |
ECs, TECs | AKI due to renal I/R injury | Negatively regulates the expression of IL-6, TNF-α, and NF-kB [82] | Negatively regulates the expression of IL-6, TNF-α, and NF-kB [29] | |
Kidney cells | CKD | Promotes pyroptosis by downregulating miR-23c [100] | Promotes pyroptosis by downregulating miR-23c [47] | |
NEAT1 | Mesangial cells | DN | Activates Akt/mTOR signaling, and represses TGF-β1, FN, and COL-IV expression [64] | Activates Akt/mTOR signaling, and represses TGF-β1, FN, and COL-IV expression [11] |
ECs, TECs | AKI due to renal I/R injury | Downregulates miR-27a-3p [83] | Downregulates miR-27a-3p [30] | |
Renal Tubular Epithelial Cell | MN | Inhibits Noxa-mediated anti-apoptotic activity [112] | Inhibits Noxa-mediated anti-apoptotic activity [59] | |
PRINS | Renal tubular cells | AKI due to renal I/R injury | Regulates the production of RANTES [84] | Regulates the production of RANTES [31] |
PVT1 | Mesangial cells | DN | Increased expression of extracellular matrix proteins [57,58] | Increased expression of extracellular matrix proteins [4][5] |
HK-2 | CKD | Is involved in the TGF-β signaling pathway [92] | Is involved in the TGF-β signaling pathway [39] | |
RP11-2B6.2 | Renal cells | LN | Intervenes in the IFN-I pathway through epigenetic inhibition of SOCS1 [113] | Intervenes in the IFN-I pathway through epigenetic inhibition of SOCS1 [60] |
TCONS_00088786, TCONS_01496394 | Kidney tissue | Tubular ischemia and CKD | Affect the expression of genes related to renal fibrosis [87,88] | Affect the expression of genes related to renal fibrosis [34][35] |
TUG1 | Podocytes | DN | Modulates mitochondrial bioenergetics [59] | Modulates mitochondrial bioenergetics [6] |
HK-2 | AKI | Interacts with Nrf2 [60] | Interacts with Nrf2 [7] | |
XIST | ECs, TECs | AKI due to renal I/R7 injury | Induces apoptosis and inflammation [80] | Induces apoptosis and inflammation [27] |
HK-2 | Renal calcinosis | Influence the expression of some inflammatory factors [96] | Influence the expression of some inflammatory factors [43] | |
Kidney tissues and cultured podocytes | MN | Proapoptotic effect through upregulation of Toll-like receptor 4 and downregulation of miR-217 [109,110] | Proapoptotic effect through upregulation of Toll-like receptor 4 and downregulation of miR-217 [56][57] | |
XLOC-032768 | HK-2 | AKI induced by nephrotoxic agents | Regulates tumor necrosis factor TNF-α [78] | Regulates tumor necrosis factor TNF-α [25] |
HK-2: Human Kidney 2; DN: Diabetic Nephropathy; TECs: Tubular Epithelial Cells; CKD: Chronic Kidney Disease; ECs: Endothelial Cells; AKI: Acute Kidney Injury; I/R: Ischemia/Reperfusion; PBMCs: Peripheral Blood Monocytes cells; IgAN: IgA Nephropathy; EMT: Epithelial-Mesenchymal Transition; PTEC: Proximal Tubular Epithelial Cells; FSGS: Focal Segmental Glomerulosclerosis; MN: Membranous Nephropathy; LN: Lupus Nephritis.
As previously described, lncRNAs also play an important role in renal pathogenesis. However, little is known about lncRNAs that are expressed in the healthy kidney and that are involved in renal cell homeostasis and development, and even less is known about lncRNAs involved in human adult renal stem/progenitor cells (ARPC) homeostasis. ARPCs constitute a very promising cell population that has great potential for the development of future treatments for both acute and chronic kidney injury. The ARPCs can be isolated from both tubules and glomeruli; they have many similar morphological and transcriptional characteristics but also important differences [124,125,126,127][61][62][63][64].
Several studies have identified long non-coding RNAs as key players in the molecular mechanisms that drive gene regulation, demonstrating that lncRNAs are involved in cellular reprogramming processes [135][65]. It became very important, therefore, to understand what the lncRNAs role is in the biology of ARPCs. Very recently, a whole-genome lncRNA expression screening was performed for the first time in ARPCs. About 611 lncRNAs that were differently regulated and capable of discriminating the ARPCs from the RPTECs were discovered. According to the pathway analysis, several lncRNA, exclusively expressed in ARPCs, were shown to be involved in the biological processes regulating the cell cycle. Among differentially modulated lncRNAs, HOTAIR was found to be a crucial component controlling these pathways. By creating HOTAIR knock-out ARPC lines, it was demonstrated how this lncRNA controls ARPC apoptosis and maintains their proliferative and self-renewal abilities.
Exploiting the CRISPR/CAS9 genome editing method, the HOTAIR fundamental function in maintaining the self-renewal and proliferation of ARPCs has been demonstrated. HOTAIR prevents ARPCs from becoming senescent in the short term by modulating the expression of the CD133 stemness marker. The renal progenitors, thanks to the high expression of HOTAIR, are able to secrete high quantities of -Klotho, an anti-aging protein capable of influencing the surrounding tissues and therefore modulating renal aging [136][66]. Emerging data have shown that certain aging-related characteristics in - Klotho deficient mice may result from stem cell depletion or stem cell differentiation to promote fibrosis; therefore, the dysfunction and depletion of stem cells and progenitor cells contribute to aging [137][67]. The lncRNA HOTAIR prevents premature depletion of the renal progenitor population in the kidney thanks also to its role in constraining the expression of the cellular inhibitor p15, helping to keep the cell cycle of these progenitor cells active; this action is carried out by methylation of histone H3K27me3 on the promoter of the p15 gene [136] [66]. Through the trimethylation of lysine 27 in histone H3 in the p15 promoter, HOTAIR suppresses the production of the protein p15 in normal ARPCs, favoring growth and self-renewal.