The Role of LncRNA in Kidney Disease: History
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Contributor:
Francesca Giannuzzi
,
Silvia Maiullari
,
Loreto Gesualdo
,
Fabio Sallustio

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).

  • long non-coding RNAs
  • renal disease
  • stem cell biology

1. Diabetic Nephropathy

Diabetic nephropathy (DN) is a chronic kidney disease that results from diabetes mellitus and is characterized by albuminuria, a decline in the glomerular filtration rate, and arterial hypertension. If left untreated, it can progress to end-stage renal disease (ESRD) [1][2]. Plasmacytoma variant translocation 1 (PVT1) was one of the first lncRNAs associated with DN. Through genome-wide SNP genotyping analyses, PVT1 was indicated as a susceptibility locus for the onset of DN and the development of ESRD [3]. High glucose content upregulated the expression of PVT1 in mesangial cells, causing increased expression of proteins that composed the extracellular matrix (ECM). Conversely, silencing of PVT1 led to a significant decrease in mRNA and major ECM proteins, such as fibronectin and collagen type IV alpha 1, as well as their transcriptional regulators, such as transforming growth factor beta 1 (TGFB1) and plasminogen activator inhibitor (PAI-1). These findings suggest that PVT1 may mediate the development and progression of DN through mechanisms involving ECM protein accumulation [4][5]. One of the mechanisms underlying the pathogenesis of DN is the disruption of mitochondrial homeostasis. Long and et al. linked the modulation of mitochondrial metabolism to the lncRNA TUG1 [6]. Specifically, they observed that TUG1 was linked to mitochondrial bioenergetics by recruitment of PGC-1α (Peroxisome proliferator-activated receptor-γ Coactivator-1 α) to its promoter. Transgenic mice that overexpressed TUG1 in podocytes were protected from diabetes-induced CKD, while glomerular TUG1 levels were reduced in both mice and renal biopsies from diabetic patients. Moreover, specific overexpression of TUG1 in podocytes from this mouse model improved the glomerular phenotype with regard to both albuminuria and histological changes. This suggests that this lncRNA may be a possible therapeutic target to treat kidney disease and/or diabetes [6][7]. Yang et al. observed that 45 and 813 lncRNAs were up- and downregulated, respectively, in the serum of DN patients compared with diabetic patients [8]. Among them, lncRNA-ARAP1-AS2 and lncRNA-ARAP1-AS1 are the ones involved in the pathogenesis of DN. LncRNA-ARAP1-AS2 gradually increases during the progression of diabetes and diabetic nephropathy, while lncRNA-ARAP1-AS1 gradually decreases. Both enhance the mRNA expression of ARAP1, a member of the renin-angiotensin system (RAS) [8][9]. Several studies indicate a functionally important involvement of NEAT1 lncRNA in diabetic nephropathy. Increased expression of NEAT1 contributes to proliferation and fibrosis in the progression of DN through activation of Akt/mTOR signaling, whereas expression of TGF-β1, FN, and COL-IV is repressed by NEAT1 in vitro [10].

2. Acute Kidney Injury

Acute kidney injury is a complex renal disorder characterized by an abrupt decline in renal function. The main triggers of AKI are sepsis, nephrotoxic insults, and ischemia-reperfusion. Despite considerable progress, the AKI pathophysiological mechanisms have not been fully explored. Numerous pieces of evidence have accumulated showing that non-coding RNAs are involved in the pathophysiology of AKI and the regulation of numerous genes, showing significant potential for the development of diagnostic and therapeutic strategies. Most studies conducted to examine lncRNAs in AKI have been performed in vivo in mice or rats by induction of urine-derived sepsis [11][12], ischemia-reperfusion injury (IRI) [13][14][15], and lipopolysaccharide (LPS)-stimulated inflammation [16][17], while the human tubular epithelial cell line HK-2, treated with LPS [11][12], or grown under hypoxic conditions [14][15][18], has been used in vitro (Table 1).
In a microarray study, it was observed that 5361 lncRNAs were upregulated and 5928 were downregulated in patients with septicemia-induced AKI. Among the various lncRNAs studied, MALAT1 and TUG1 also occur. MALAT1 expression is increased in the serum of patients with sepsis, in the kidney tissue of experimental animals, and in LPS-treated kidney cells. MALAT1 promotes renal damage by activating nuclear factor-κB (NF-κB). Accordingly, silencing of MALAT1 showed a significant renal protective effect [16]. In contrast to the above-mentioned lncRNA MALAT1, overexpression of TUG1 showed a protective effect in LPS-treated HK-2 cells by modulating the NF-kB gene [19] and through the interaction with the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor [20]. In addition, HOXA-AS2 lncRNA showed protection in sepsis-caused AKI by hindering Wnt/β-catenin and NF-κB pathways [21]. In addition, overexpression of lncRNA6406 attenuates cellular inflammation, oxidative stress, and apoptosis through modulation of miR-687/PTEN signaling [22][23]. XLOC-032768 and LRNA9884 lncRNAs were studied in AKI induced by nephrotoxic agents in vivo and in vitro. Zhou et al. demonstrated that overexpression of lncRNA XLOC-032768 reduced apoptosis and TNF-mediated inflammation in mice and cells exposed to cisplatin [24], while Zhang et al. showed that LRNA9884 was markedly upregulated in the nucleus of the renal tubular epithelium in mice with AKI and promoted inflammatory cytokine production via NF-κB [25].
Another important cause of AKI is ischemia/reperfusion (IR). XIST, NEAT1, MALAT1, and H19 lncRNAs have been found upregulated in human biopsies of AKI, in experimental models of IR, and in cultured hypoxic endothelial and tubular cells [26][27][28][29] (Table 1). Increased lncRNA XIST (X inactive specific transcript) in IR-damaged kidneys and renal cells induces apoptosis and inflammation [26]. NEAT1 induces apoptosis of renal tubular epithelial cells through downregulation of miR-27a-3p, identifying this miRNA as a target of NEAT1 [29]. Overexpression of H19 lncRNA improved renal function and angiogenesis and decreased inflammation and apoptosis through upregulation of miR-30a-5p [27]. The upregulation of MALAT1 was activated by hypoxia-inducible factor 1-α (HIF-1α) and negatively regulated the expression of IL-6, TNF-α, and NF-kB [28]. The lncRNA PRINS is involved in the AKI process by regulating the production of RANTES, a major inflammatory mediator of AKI following IR injury. Increased levels of RANTES in renal tubular cells further aggravated renal injury through recruitment of inflammatory cells and led to loss of renal function after IR injury [30].

3. Chronic Kidney Disease

CKD is a disease characterized by hypoperfusion-induced tubular ischemia, interstitial fibrosis, and impaired renal function [31][32]. Additionally, in this case, several lncRNAs that can regulate the expression of some CKD-related genes and proteins, such as collagen, smooth muscle α-actinin, and fibronectin, have been identified (Table 1). For example, the lncRNAs TCONS_00088786 [33] and TCONS_01496394 [34], which are regulated by TGF-β stimulation, can influence the expression of some fibrosis-related genes through a feedback loop. Similarly, lncRNA Erbb4-immunoreactivity (Erbb4-IR) is induced by TGF-β1 and highly upregulated in fibrotic kidneys. The silencing of Erbb4-IR blocks TGF-β1–induced collagen I and α–smooth muscle actin expression in vitro [35] and up-regulates Smad7 in the kidneys, thereby attenuating TGF-β1/Smad3-induced renal fibrosis in vivo and in vitro [36][37].
PVT1 lncRNA is mainly regulated by the miR-181a-5p/TGF-βR1 signaling pathway. The expression of PVT1 lncRNA is significantly upregulated in renal fibrosis. Knockdown of lncRNA PVT1 inhibited the progression of renal fibrosis via regulation of TGF-β signaling, downregulation of the expression of α-SMA, upregulation of the expression of E-cadherin, and via miR-181a-5p [38]. H19 lncRNA, together with miR-17 and fibronectin, forms a regulatory network involved in renal fibrosis [39]. Its expression has been significantly correlated with oxidative stress and inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in patients with CKD [40][41].
Other lncRNAs may influence the expression of some inflammatory factors and are associated with the production of and defense against reactive oxygen species (ROS). The lncRNA XIST (X inactive specific transcript) attenuates renal inflammation, and ROS production induces oxidative damage in renal calcinosis [42]. In addition, lncRNAs can drive renal fibrosis by regulating several biological processes, such as apoptosis, cell proliferation, autophagy, and epithelial-mesenchymal transition (EMT). One example is LINC00667 lncRNA, which reduces the proliferation and invasion of CKD cells while increasing the rate of apoptosis [43][44]. LncRNA 74.1 was significantly downregulated in clinical samples of renal fibrosis and promoted ROS defense by activating prosurvival autophagy, then reducing ECM-bound proteins fibronectin and collagen I involved in renal fibrosis [45].
LncRNAs are also involved in another important mechanism of pathological damage in CKD called pyroptosis. This process is a particular type of programmed cell death that includes some features of apoptosis and necrosis. The lncRNAs MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) promote pyroptosis through downregulation of miR-23c, while GAS5 (growth arrest-specific 5) has anti-pyroptotic properties [26][46].

4. Glomerulonephritis

LncRNAs have been involved in different kinds of glomerulonephritis (Table 1). Focal segmental glomerulosclerosis is a common kidney disease resulting from the dysfunction and apoptosis of podocytes in the glomerulus of the kidney. Compared with DN, little is known about the contribution of lncRNAs to this glomerular disease. One of the lncRNAs associated with FSGS is lncRNA LOC105375913 [47], whose increased expression promotes snail overexpression and tubulointerstitial fibrosis. Upregulation of lncRNA LOC105374325, related to activation of the P38/C/EBPβ pathway in podocytes of individuals with FSGD, increases the level of Bax and Bak genes and causes cell apoptosis [48].
IgA nephropathy is one of the most common primary glomerulonephritis and is characterized by immune complexes (IC) formed mainly by IgA that are deposited in the mesangial area of the glomerulus, causing glomerular inflammation and further renal damage [49]. About 217 lncRNAs differentially expressed in peripheral blood monocyte cells (PBMCs) have been suggested as potential factors involved in the pathophysiology of IgA nephropathy [50]. Among them, HOTAIR has been the most important lncRNA in the regulation of differentially expressed genes/miRNAs in IgA nephropathy [50]. In another study, the lncRNA-G21551 was observed to be significantly down-regulated in IgAN patients and could play an important role in the pathogenesis of IgAN by regulating the expression of FCGR3B, a gene that encodes for the low affinity receptor (FcgR3B receptor) of the Fc segment of immunoglobulin G (IgG) [51]. Moreover, the lncRNA PTTG3P levels have been found higher in IgAN samples than in healthy subjects. Overexpression of PTTG3P induced B-cell growth, increased the expression of cyclin D1 and Ki-67 genes, and induced the production of IL-1β and IL-8, which play key roles in the onset and development of IgAN [52]. Some lncRNAs may be used as disease biomarkers. The expression of the lncRNA MYEF2-1.1 was 85-fold lower in IgAN patients than healthy controls, while that of ALOX15P1-ncNR045985 was 5.15-fold higher [53]. Wen et al. have observed a significant increase in intercellular adhesion molecule-1 (ICAM-1)-related lncRNA (ICR) levels in kidney tissue from patients with IgAN. This lncRNA is involved in the renal fibrotic processes; indeed, its inhibition attenuated the fibrotic changes in TGF-β1-induced renal proximal tubular cells through reduction of phosphorylation and consequent inhibition of the Akt/mTOR signaling pathway [54].
lncRNA XIST has been linked to membranous nephropathy [55][56], a kidney-specific autoimmune disease [57]. Its upregulation in a mouse model of MN and in human samples [56] has been associated with a proapoptotic effect on podocytes through upregulation of Toll-like receptor 4 and negative regulation of miR-217 [55]. Upregulation of NEAT1, on the other hand, promotes MN development by inhibiting the anti-apoptotic activity mediated by Noxa (a Bcl-2 homolog 3 protein) to induce apoptosis [58]. Finally, the lncRNA RP11-2B6.2 was found to be increased in the renal tissue of patients with lupus nephritis compared with healthy controls. Overexpression of RP11-2B6.2 led to inhibition of SOCS1, resulting in hyperactivation of the IFN-I signaling pathway in renal cells [59]. Among the many pathogenic signaling pathways identified in LN, hyperactivation of the IFN-I response is closely associated with disease progression and prognosis [60].
As noted so far, numerous studies have been conducted and knowledge gained on lncRNAs in the renal field in recent years, not only for their involvement in the pathophysiology of renal diseases but also for their potential as diagnostic and prognostic biomarkers and therapeutic targets. In addition, it is noteworthy that by analyzing lncRNA studies performed on renal diseases (Table 1), the researchers can identify six lncRNAs involved in more than one type of renal disease, in particular PVT1, TUG1, NEAT1, MALAT1, XIST, and H19. Among these, PVT1 and XIST have a common mechanism on multiple kidney diseases, the first increasing the expression of extracellular matrix proteins through the TGFB and the second inducing apoptosis. The other four lncRNAs may have different mechanisms for each disease. Instead, this may be due to the type of study performed or the choice of the authors to study only a specific mechanism. Moreover, several lncRNAs have been found to be expressed only in one kind of renal disease. Additionally, in this case, it may depend on the type of study and on the experimental setting performed. However, despite considerable progress, there are still many unclear mechanisms and countless puzzles to be solved before study results can be promoted to the clinical level.
Table 1. Long non-coding RNAs in renal disease.
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 [9][10]
ENST-00000453774.1 HK-2 CKD 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 [36]
GAS5 Kidney cells CKD Has anti-pyroptotic properties [47]
H19 ECs, TECs AKI due to renal I/R injury Upregulates miR-30a-5p [28]
HK-2 CKD Affects TNF-α and IL-6 expression [40][42]
HOTAIR PBMCs IgAN 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 [22]
ICR Renal Proximal Tubular Cells IgAN Is involved in the Akt/mTOR signaling pathway [55]
LINC00667 Renal Tubular Epithelial Cell CKD 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 [26]
lncRN A6406 PTEC AKI Modulates miR-687/PTEN signaling [23][24]
lncRNA G21551 Exosomes IgAN 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 [53]
LOC105375913 Renal tubular cells FSGS Increases the level of snail and tubulointerstitial fibrosis [48]
LOC105374325 Podocytes FSGS Increases the level of Bax and Bak genes and causes cell apoptosis [49]
MALAT1 HK-2 AKI 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 [29]
Kidney cells CKD Promotes pyroptosis by downregulating miR-23c [47]
NEAT1 Mesangial cells DN 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 [30]
Renal Tubular Epithelial Cell MN Inhibits Noxa-mediated anti-apoptotic activity [59]
PRINS Renal tubular cells AKI due to renal I/R injury Regulates the production of RANTES [31]
PVT1 Mesangial cells DN Increased expression of extracellular matrix proteins [4][5]
HK-2 CKD 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 [60]
TCONS_00088786, TCONS_01496394 Kidney tissue Tubular ischemia and CKD Affect the expression of genes related to renal fibrosis [34][35]
TUG1 Podocytes DN Modulates mitochondrial bioenergetics [6]
HK-2 AKI Interacts with Nrf2 [7]
XIST ECs, TECs AKI due to renal I/R7 injury Induces apoptosis and inflammation [27]
HK-2 Renal calcinosis 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 [56][57]
XLOC-032768 HK-2 AKI induced by nephrotoxic agents 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.

5. The Role of lncRNA HOTAIR in Human Adult Renal Stem/Progenitor Cells

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 [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 [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 [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 [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 [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.

This entry is adapted from the peer-reviewed paper 10.3390/cells12081115

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