Acute kidney injury (AKI) is a severe clinical syndrome characterized by an abrupt decrease in kidney function, as measured by high blood creatinine and decreased urine volume within 7 days (Kellum et al., 2012). Epidemiologic studies have found that about 13.3 million people worldwide suffer from AKI each year (Mehta et al., 2015). Furthermore, the global health burden of AKI-related mortality is far beyond that of breast cancer, heart failure, or diabetes (Lewington et al., 2013). Therefore, finding effective prevention and treatment approaches are indispensable. Clinically, the cause of AKI can be divided into three categories: pre-renal (impaired renal perfusion), intra-renal, and post-renal (urinary tract obstruct). Among these, sepsis, and ischemia/reperfusion (I/R) are the common leading causes of AKI. Besides, post-contrast AKI (CI-AKI), transplant-related AKI, and drug or toxin induced AKI have become prevalent and important as medical care evolves as well. The pathogenesis of AKI is multifactorial and has been overwhelmingly implicated in the etiology of AKI (Kinsey and Okusa, 2011).

Even though our understanding of the pathophysiology of AKI is continually expanding, the precise processes remain unknown. Following the improvements and cost reductions of high throughput RNA-sequencing, considerable research has reported that the non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), are strongly associated with the pathophysiological process underlying AKI. As the quantity of research on lncRNAs has grown fast, in order to offer a thorough and up-to-date overview of the function of lncRNAs in AKI, we briefly introduce the lncRNA and systematically review the mechanism of functional lncRNAs in AKI due to various etiologies. Finally, we highlight certain aspects of the lncRNA mechanism in AKI, as well as future research directions.

LncRNAs are a subtype of ncRNA that longer than 200 nt with no protein-coding potential and make up the most considerable portion of the mammalian non-coding transcriptome (Mercer et al., 2009; Derrien et al., 2012). Sequence analysis of lncRNAs between different species revealed that lncRNAs presented the characteristics of low DNA sequence conservation and low expression. Commonly, according to lncRNA location concerning protein-coding genes, lncRNAs could be classified as either intergenic or intragenic. Intergenic lncRNAs do not intersect with any protein-coding genes. In contrast, intragenic lncRNAs overlap with protein-coding genes and could be further sorted into antisense, bidirectional, intronic, and overlapping sense lncRNAs. In parallel, lncRNAs could also be categorized based on their length, location, transcript properties, regulatory mechanisms, function, and so on (Statello et al., 2021).

Most lncRNA species are transcribed by Pol II. It also could be capped, spliced, and polyadenylated, exported like mRNA. However, after being transcribed by Pol II, lncRNAs will further fold into the complex secondary or tertiary structures. Those high-ordered structures showed higher conserved than their primary sequence. Diversified structure enables lncRNAs to participate in life activities and disease progress by interacting with DNA, RNA, or protein to regulate gene expression at multiple levels (epigenetic regulation, transcription regulation, and post-transcriptional regulation). Among these, research on the roles of lncRNAs in post-transcriptional regulation has been investigated the most. Three major mechanisms of lncRNA regulate the gene expression in post-transcriptional: a. binding to RNA or structures to form a lncRNA-protein complexes directly; b. pairing with the other RNAs to recruit proteins; c. competing endogenous RNAs or ‘sponges’ of miRNAs to restrict miRNA availability to target mRNAs (Marchese et al., 2017; Salviano-Silva et al., 2018). Aside from the structure, the location of lncRNAs in cells also exerts an intensive effect on their functions (Chen, 2016). In addition to being located in the nucleus, lncRNAs have been detected in additional subcellular sites such as mitochondria and exosomes (Bridges et al., 2021). Moreover, these organelle-specific lncRNAs are intensively implicated in organelle homeostasis, which is always plays a role in the occurrence and development of the disease (Li et al., 2021b).

Currently, research methodologies for investigating the functions of lncRNAs in disease include lncRNA identification, lncRNA characteristic analysis, functional investigations, and molecular processes (Gao et al., 2020a). Similarly, advances in experimental equipment and computational methodologies in lncRNAs study have occurred in recent years. Among these advancements, fully functional sequencing databases stands out. First, with the introduction of third generation sequencing technology and lncRNAs databases, lncRNA screening has grown completer and more reliable. Second, emerging bioinformatics algorithm, database RACE, and fluorescence in situ hybridization (FISH) offer great assistance in annotating the characteristic of lncRNAs, such as coding potential, location information on the genome, secondary structure, correlation with the diseases, full-length analysis, and cell localization (Liu et al., 2018). Then, the roles of lncRNAs are generally validated by overexpression or Knock down of specific lncRNAs, and their role in diseases development is studied by assessing changes in biological behaviors in vitro and in vivo tests. Finally, by combining the prediction work of databases and experiment technology such as DNA-FISH (Gelali et al., 2019), chromatin immunoprecipitation (Nakato and Sakata, 2021), RNA-pull down, luciferase reporters (Cao et al., 2019), and methylation-specific PCR (Hernández et al., 2013), the specific molecular regulation network between the protein, RNA, or DNA, and the lncRNAs could be illustrated.

Based on the strategies and technologies mentioned above, studies have identified that lncRNAs serve a crucial role in various biological processes, ranging from the cell cycle, growth, apoptosis, and immune responses to some tissue-specific physiology. Many lncRNAs have been verified to have links with prevalent diseases, such as cancer, neurological and cardiovascular diseases (Fenoglio et al., 2013; Peng et al., 2017; Fernandes et al., 2019). Simultaneously, increased emphasis has been placed on the significance of lncRNAs in renal disorders.

Post-contrast acute kidney injury (PC-AKI), also called contrast-induced acute kidney injury (CI-AKI), is a kind of kidney disease that the renal function deteriorates suddenly within 48 h of intravascular administration of contrast medium (van der Molen et al., 2018). Data have shown that PC-AKI was the third most common cause of AKI in hospitalized patients (Nash et al., 2002) and accounted for high mortality rates (Levy et al., 1996). More recently, the literature has emerged that offers significant findings of the definition, risk factors, pathophysiology mechanism, and medical intervention of PC-AKI (Mehran et al., 2019; Bansal and Patel, 2020; Everson et al., 2020). Bioinformatics analysis revealed that lncRNAs could serve as novel biomarkers in the early phase of PC-AKI (Table 3). Chen et al. depicted the expression landscape of lncRNAs and identified 357 differentially expressed lncRNAs in PC-AKI. Among these, lnc-HILPDA and lnc-PRND, which were conservative and remarkably up-regulated in both kidneys and blood from rats and the blood of PC-AKI patients, can effectively predict PC-AKI risk and precisely distinguish PC-AKI patients after the exposure to contrast medium (Chen et al., 2021a).

Since the expression of lncRNAs has undergone massive changes in PC-AKI, more and more researchers are delving into the specific regulatory mechanism that lncRNA is involved in PC-AKI. Cheng and coworkers systematically explored the lncRNA-associated-ceRNA regulatory network in rats with PC-AKI by RNA-seq analysis and two constructed ceRNA regulatory pathways in the CI-AKI rat model (novel_circ_0004153/rnomiR-144-3p/Gpnmb or Naglu and LNC_000343/rno-miR-1956-5p/KCP) were reported firstly and validated by real-time qPCR. Further function annotation shows that the disease-specific lncRNAs may participate in physiological and pathological processes of PC-AKI from different aspects, including porphyrin-containing compound metabolic, biosynthetic processes, heme binding, and so on (Cheng et al., 2019). Another study also found and verified that differential expressed lncRNAs and their co-expression targets were associated with vital pathological pathways of PC-AKI, like inflammation and oxidative stress (Bao et al., 2021). For instance, they identified a group of lncRNAs (such as MSTRG.11448.4, MSTRG.2420.1, MSTRG.6245.1, and NONRATT023367.2) linked to glycoprotein non-metastatic melanoma protein, which can negatively regulate inflammation in AKI. Furthermore, lncRNA-associated ceRNA analysis revealed a Cndp1-specific network that was also likely to be related to the process of antioxidation, which plays a vital role in oxidative stress-mediated injury in PC-AKI (Ripoll et al., 2007; Zhou et al., 2017b). In summary, although hundreds of lncRNAs associated explicitly with the PC-AKI have been identified and several studies have constructed their regulatory networks with other RNAs, the specific biological functions and detailed mechanisms of the vast majority of lncRNAs remain unclear, and further research in this area is required.

Kidney transplantation is one of the effective treatments for patients with end-stage renal disease (ESRD). However, as a potentially severe complication, post-transplant AKI still maintains high morbidity and mortality rates (Mittal and Kohli, 2014). The pathogenesis of post-transplant AKI is complex. Several researchers have found the association between lncRNA and post-transplant AKI (Table 3).

In 2013, Sui et al. integrated protein array-based proteomics and RNA microarray-based genomics to investigate the transcription factors (TF), miRNAs, long noncoding RNA of biopsies of three patients with acute rejections. They discovered that among the 32 differentially expressed lncRNAs, FXYD1 and HOXA11 were targeted individually by the lncRNAs Uc002nyb and Uc003syy, which were linked to a poor outcome in acute rejections (Sui et al., 2013). Another study also used lncRNA microarrays to compare the lncRNA expression in kidney biopsy from acute rejection following kidney transplantation. After validating the microarray results by qRT-PCR and screening in the five databases, the functions of five candidate lncRNAs (AF113674, uc003wbj, uc010ftb, uc001fty, and AK129917) were further defined by their location to the gene on the genome (Chen et al., 2014). Other studies have investigated the correlation between post-transplant AKI-specific lncRNA expression and the diagnosis or prognosis of acute rejection. LncRNA AF264622 and AB209021 exhibited excellent diagnostic performance both in pediatric and adult renal transplants (Ge et al., 2017). Furthermore, lncRNA MIR155HG, which participates in allograft rejection associated pathways, such as graft versus host disease, T-cell and B cell receptor, signaling pathways, can predict the risk of graft loss effectively (Zou et al., 2019).

Notably, lncRNAs are also released and circulated in the plasma, urine, and other body fluids. Investigators have also found lncRNAs in blood or urine that could be used for early detection of post-transplant AKI (Lorenzen et al., 2015; Ge et al., 2017). However, studies describing the mechanism of lncRNA in post-transplant AKI are limited. LncRNA-ATB, a novel lncRNA activated by TGF-β, may contribute to kidney transplantation survival through mediating the TGF-β signaling pathway. In this study, the expression of lncRNA-ATB was largely up-regulated in the TGF-β treated human tubule cells, activating cell proliferation and cyclosporine A-mediated apoptosis of renal cells via the downregulation of miR-200c (Qiu et al., 2017). Another up-regulated lncRNA in the serum of a post-transplant patient with AKI is XIST which could serve as a ceRNA to sponge hsa-miR-212-3p to regulate inflammation and apoptosis in the progression of AKI via modulating the expression of ASF1A and BRWD1. Furthermore, lncRNA XIST could also sponge miR-122-5p to influence thyroid hormone and AMPK signaling via modulating the expression of PFKFB2 in AKI (Cheng and Wang, 2020).

Overall, these studies reasonably provide consistent evidence of an association between lncRNA and post-transplant AKI. Most current research on lncRNA remains at the level of their expression pattern identification and diagnostic or prognostic potential in diseases. There is still much room for improvement, and more attention should be paid to their therapeutic potential.

Aside from the four types of AKI mentioned above, medication or toxin-induced AKI is a kind of AKI that is common in the clinic but poorly understood in lncRNA-based biological mechanism research. Upon closer inspection of the literature， We identified only six relevant papers investigating the role of lncRNA in cisplatin reduced AKI. At the same time, no study reports the relationship between lncRNAs in other common drug-induced AKI, such as aristolochic acid, folic acid, and antibiotics for the time being (Table 3). Among them, lncRNA9884 is a promoting factor of cisplatin induced AKI. Expression elevated lncRNA9884 could significantly aggravate tubular epithelial cells injury by activating inflammatory signaling pathway NF-κB/macrophage migration inhibitory factor (Zhang et al., 2020a). Another recent study has described that the lncRNA MEG3 could promote cisplatin-induced nephrotoxicity through regulating AKT/TSC/mTOR-mediated autophagy, and LncRNA GAS5 could aggravate renal epithelial cell apoptosis in cisplatin-induced AKI by regulating miR-205-5p (Jing et al., 2021; Zhang et al., 2021).

One study found that lncRNA OIP5-AS1 was significantly downregulated in cisplatin-induced AKI model both in vitro and in vivo. Further research revealed that OIP5-AS1 could reduce the apoptosis of cisplatin-stimulated renal epithelial cells to exert a protective effect by targeting the miR-144-5p/PKM2 axis (Chang et al., 2021a). Similarly, the novel lncRNA XLOC_032768 and PRNCR1 could also perform a similar role of reducing cisplatin-induced apoptosis of renal tubular epithelial cells to protect against the cisplatin-induced AKI through TNF-α and miR-182-5p/EZH1, respectively (Zhou et al., 2020; Li et al., 2021a). Regrettably, as for the other reasons induced AKI, for instance, rhabdomyolysis-associated AKI and trauma associated AKI, the biological mechanism of those diseases has been studied, but not for the role of lncRNAs.

LncRNAs offer a novel direction for pathophysiological study and the search for new therapeutic targets in acute kidney injury. On the one hand, lncRNAs exhibit the potential to act as biomarkers for the early diagnosis and prognosis of patients with AKI. On the other hand, lncRNAs have been identified as the key mediators that participated in the pathophysiology of AKI caused by different reasons. Expression, function, and regulation network of lncRNAs altered depending on the causes of AKI. Several identified lncRNAs, such as XIST, MALAT1, NEAT1, and so on, contribute to kidney injury in two or more different reasons caused AKI through different regulatory mechanisms. Those lncRNAs may represent the potential therapeutic target for the AKI. Besides, based on the ceRNA regulatory network, one lncRNA can be involved in the different signaling pathways and link with different targets downstream, which are closely related to the process of cell apoptosis, inflammation, such as NF-κB, WNT, and PTEN (Figure 2). This feature greatly enriched and complicated the regulatory mechanism of lncRNA and provided a way to develop new therapeutic solutions for AKI.

Although the function and the diagnostic and prognostic roles of lncRNAs in AKI had been carried out extensively, the limitations are also evident in the current study. First, most studies of lncRNA function were based on the ceRNA network, which could only reveal lncRNA function at the post-translational level, possibly because of the use of bioinformatics to predict the functions of lncRNAs is preferred over traditional, time-consuming, and expensive experimental methods. Neither the function of lncRNAs at the epigenetic level or transcription level, nor the cell organelle-specific function of lncRNAs gained equitable attention in lncRNAs in AKI. Second, the specific mechanisms of various studies are still unclear, and more in-depth research is needed to reveal the relevant mechanisms. Finally, clinical trials to validate the therapeutic potential of lncRNAs in AKI are currently inadequate due to the lack of a safe and effective delivery mechanism. There is still a long way to go before the study results can be promoted clinically. For sure, some difficulties exist in the lncRNAs research due to the low expression, low sequence conservation, and diverse secondary functional structure of the lncRNAs. Thus, in the future, the more credible algorithms need to be developed, the more precise detection technology of lncRNAs needs to be innovated, the more safe and efficient drug delivery method needs to be devised. In summary, there remains a huge gap in access to a comprehensive understanding of LncRNAs in AKI, and further efforts will be needed.

LY and BW defined the subject, revised the literature, and wrote the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by the National Key R&D Program of China (2020YFC2005000). Figures 1 and 2 were created with a free version of Biorender.com

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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