miR-21 in Kidney Injuries and Diseases: Comparison
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miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases. In contrast with normal kidney function, miR-21 switches to a powerful and overactive mediator under stress conditions. In particular, miR-21 is one of the most highly upregulated miRNAs in a wide panel of tissue injuries, and may act as a cellular sensor of injuries that mediates tissue regeneration.

  • microRNA
  • kidney
  • cancer
  • fibrosis

1. miR-21 in Acute and Chronic Kidney Diseases

miR-21 has been associated with the development of a large number of both acute and chronic renal diseases. These studies consistently report a ubiquitous and non-specific increase of miR-21 renal expression in both acute and chronic renal diseases. Numerous experimental models have also explored the role of miR-21 using animal models of acute renal failure or chronic kidney diseases.

1.1. A Protective Role of miR-21 in Acute Kidney Injury?

Acute renal diseases are mainly represented by acute tubular necrosis (ATN), whose causes, although variable, are often related to two main mechanisms: ischemia (induced by hypovolemia, hemorrhage...) and iatrogeny (aminoglycosides, iodine, renin-angiotensin system blockers, cisplatin...) [1]. The evaluation of renal miR-21 expression in clinical samples remains patchy, due to the fact that renal biopsies are rarely performed, except for in the context of renal transplantation [2]. ATN is mainly associated with an increased miR-21 level in renal tissue, serum, or urine of patients with ATN [2][3][4][5]. Furthermore, a large number of ATN-mimicking animal models rely on ischemia-reperfusion mouse models [3][6][7][8][9][10][11][12][13][14][15] or the administration of nephrotoxic compounds, mainly gentamycin [3][10] or cisplatin [16]. All of these models demonstrated an early increase of miR-21 renal expression [13] that may be prolonged up to 30 days after injury [7]. Following repeated low-intensity injuries, miR-21 increase could thus initially plays a protective role, inducing wound healing and tissue regeneration processes by targeting PTEN [5], PDCD4 [8], PHD2 [15], the MKK3–MAPK–p38 pathway [13], thromospondin-1 [14] and Rab11A [11]. However, there is conflicting evidence regarding the protective or deleterious nature of miR-21. Indeed, in most studies, the inhibition of miR-21 leads to histological damage worsening and decreased renal function [8][10][11] after ischemia reperfusion, even if a protective preconditioning intervention, such as cobalt chloride injection [15], Xenon inhalation [10] or ischemic preconditioning [8], was beforehand applied. By contrast, Chau et al. reported that miR-21 inhibition improves histological injuries and albuminuria seven days after ischemic injury [6]. The main elements that may explain the difference between those studies are the variable miR-21 inhibitor injection schedule and endpoints (in particular euthanasia delay post-injury). We can thus hypothesize that miR-21 plays a protective role at the early stage of ischemia-reperfusion lesions, in particular in preconditioning interventions, but plays a secondary deleterious role once ATN lesions have been initiated.

1.2. Sustained and Persistent Expression of miR-21 Has a Deleterious Impact in Chronic Kidney Diseases

miR-21 has been shown to be elevated in renal tissue, blood or urine in clinical samples from various pathologies. As is consistent with most studies, a miR-21 increase is associated with more severe damages [17][18][19][20][21][22][23][24]. Similarly, an increased expression of miR-21 is unanimously reported in a plethora of chronic kidney disease mouse models, underlining the deleterious role of miR-21 in chronic kidney diseases, including diabetic nephropathy [25][26][27][28][29], unilateral ureteral obstruction [6][25][30] and Alport syndrome [31].
It is noteworthy that most disparate diseases, such as diabetes mellitus, hypertension, Alport Syndrome or acute renal injuries, result in the development of either glomerular or interstitial fibrosis. Converging evidence from computational, biochemical and genetic experiments has indeed shown that miR-21 is a genuine profibrotic miRNA, regardless of the injured organ. In particular, miR-21 is invariably upregulated during the fibrogenic response to tissue injury and promotes the TGF-β signaling pathway, the major driver of tissue fibrosis [32]. In particular, Chau et al. produced a miR-21-null mouse to investigate the role of this miRNA in kidney fibrosis [6]. As is consistent with previous findings reported in cardiac [33] and lung fibrosis [34], injured kidneys from miR-21-deficient mice exhibited less fibrosis. Unexpectedly, the authors further showed that miR-21 primarily regulates the genes involved in lipid metabolism and mitochondrial redox regulation, rather than genes implicated in matrix turnover, inflammation or innate immunity. Indeed, the authors identified PPAR-α, a major transcription factor that regulates a number of lipid oxidation and metabolism pathways, and Mpv17l, which is thought to inhibit ROS formation by mitochondria, as direct targets of miR-21 [6]. This distinct mechanism was explained by the identification of epithelial cells as the major cellular source of increased miR-21 expression. Of particular interest, this study highlights that miR-21 can drive fibrogenesis by several distinct mechanisms, depending on the cellular context (Figure 1).
Figure 1. Role of miR-21 in kidney diseases. Following injury, the expression of miR-21 is increased in renal cells. miR-21 promotes kidney diseases by repressing various target genes. Levels of miR-21 can be assessed in urine or blood samples as a biomarker of kidney injury. Given its established pathogenic role in kidney disorders, targeting miR-21 using antisense oligonucleotides may represent a new therapeutic strategy for renal diseases.

2. miR-21 as an “oncomiR”

miRNAs influence numerous cellular processes, including cell cycle regulation, differentiation and apoptosis, and can therefore act as either tumor suppressors or oncogenes [35]. Consequently, alterations in miRNA gene expression have a major impact on tumorigenesis. In particular, the overexpression of miR-21 is associated with many forms of cancer, and functional studies have established this miRNA as a genuine oncomiR (Figure 1). Indeed, many studies have demonstrated that miR-21 has a central role in tumor initiation and progression by targeting critical tumor suppressive genes, such as PTEN or PDCD4. Not surprisingly, comprehensive studies assessing miRNA expression in renal cell carcinoma (RCC) have shown widespread miRNA dysregulation, with many of these aberrantly expressed miRNAs targeting components of key oncogenic networks associated with RCC, including the HIF-, TGF-β- or mTOR-signaling pathways. Several studies on RCC have shown that miR-21 is overexpressed in the clear cell (cRCC) and papillary (pRCC) subtypes of RCC tumors compared with healthy kidneys and benign renal tumors [35][36][37][38][39][40][41]. In cRCC tissue patients, there is no relationship between miR-21 expression and age, laterality or gender [40][41]. Chen et al. have shown, in a cohort of 104 RCC tissue samples, that a higher miR-21 level is associated with larger tumor size, more lymph node metastasis and an advanced TNM stage [41]. In contrast, another study has shown in a cohort of 99 cRCC tissue samples that miR-21 expression was not associated with stage, nuclear Fürhman grade nor patient outcome [40]. Thus, miR-21 expression alone in primary tumors seems of limited interest as a diagnostic or a prognostic biomarker, and should rather be included in miRNA signature [42][43][44][45]. Furthermore, miR-21 is also detected in RCC patient serums, and could be used as biomarker but only in combination with other miRNAs, such as miR-106a, miR-310-3p, miR-150-5p and miR-145-5p [46][47][48]. cRCC accounts for 70–85% of all RCC cases, and is typically highly resistant to conventional therapies [49][50]. Studies from the TCGA uncovered that the altered promoter methylation of miR-21 is associated with aggressive cRCC, suggesting that miR-21 may exert an important oncogenic function in this neoplasia [37][51]. miR-21 is not only upregulated in cRCC but is also involved in cancer progression (proliferation, migration, invasion, epithelial mesenchymal transition) and the cancer stem cell phenotype by targeting tumor suppressor genes such as PTEN, PDCD4, TIMP3 or LATS1 [40][41][52][53][54][55][56][57][58][59][60]. As cRCC is typically highly resistant to conventional systemic therapies [49][50], the identification of new molecular mechanisms driving tumor progression is essential for the rational design of new therapeutic strategies to cure cRCC. In this context, miR-21 has been shown to be involved in the resistance to conventional chemotherapies (paclitaxel, 5-Fluorouracil, topotecan and platinum-based therapy) and targeted therapies such as dovitinib and sorafenib by controlling the expression of genes associated with multi-drug resistance (MDR) and the apoptotic pathway (PTEN, PDCD4) [41][61][62]. Similar to renal fibrosis, miR-21 seems to also be involved in the metabolic shift characterizing renal cancer by targeting PPAR-α, a master regulator of lipid metabolism [63]. miR-21 silencing using antisense oligonucleotide or miR-21 sponge strategies decreases the proliferation, invasion and migration of cRCC cells and also increases the expression of pro-apoptotic markers. Furthermore, the inhibition of miR-21 enhances the sensitivity of cRCC cells to conventional genotoxic drugs, as well as to targeted therapies [40][61][62]. Finally, the inhibition of miR-21 also decreases the expression of MDR genes by a mechanism that remains to be deciphered.

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