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Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases

Human Genomics volume 18, Article number: 125 (2024) Cite this article

Abstract

Kidney disease is marked by complex pathological mechanisms and significant therapeutic hurdles, resulting in high morbidity and mortality rates globally. A deeper understanding of the fundamental processes involved can aid in identifying novel therapeutic targets and improving treatment efficacy. Current comprehensive data analyses indicate the involvement of methyltransferase-like 3 (METTL3) and its role in RNA N6-methyladenosine methylation in various renal pathologies, including acute kidney injury, renal fibrosis, and chronic kidney disease. However, there is a paucity of thorough reviews that clarify the functional mechanisms of METTL3 and evaluate its importance in enhancing therapeutic outcomes. This review seeks to systematically examine the roles, mechanisms, and potential clinical applications of METTL3 in renal diseases. The findings presented suggest that METTL3 is implicated in the etiology and exacerbation of kidney disorders, affecting their onset, progression, malignancy, and responsiveness to chemotherapeutic agents through the regulation of specific genetic pathways. In conclusion, this review underscores a detrimental correlation between METTL3 and kidney diseases, highlighting the therapeutic promise of targeting METTL3. Additionally, it offers critical insights for researchers concerning the diagnosis, prognosis, and treatment strategies for renal conditions.

Background

The incidence of renal disorders, including acute kidney injury (AKI) and chronic kidney disease (CKD), impacts approximately 10–13% of the global populace. This condition ranks as the third primary cause of mortality globally, representing a considerable public health challenge due to its high morbidity and mortality rates, along with rising healthcare costs [1]. The underlying mechanisms of AKI and CKD are complex and not fully understood, presenting substantial hurdles in management [1]. Therefore, exploring the mechanisms from novel perspectives may solve such problems.

N6-methyladenosine (m6A) modification governs post-transcriptional gene regulation and emerges as a crucial regulator of various biological processes, including RNA metabolism, cellular differentiation, and response to environmental stimuli [2]. Recent studies have highlighted its dynamic nature, where m6A methylation can be rapidly added or removed by methyltransferases and demethylases, respectively [3,4,5]. This reversibility suggests a sophisticated level of regulation that allows cells to adapt their gene expression profiles in response to changing conditions. Moreover, the interplay between m6A modification and other epitranscriptomic marks presents an intriguing area for further research. For instance, the relationship between m6A and RNA-binding proteins could elucidate how m6A influences RNA stability and translational efficiency. Understanding these interactions may also shed light on the mechanisms underlying various diseases, particularly kidney diseases, where m6A dysregulation has been implicated from AKI to CKD [6,7,8]. This regulatory mechanism is mainly controlled by methyltransferase-like 3 (METTL3), which is the active subunit responsible for the catalytic modification of RNA m6A, specifically by methylating adenine residues in post-transcriptional RNAs [9]. METTL3 influences various cellular processes through the regulation of gene translation and silencing, functioning both with and without its methyltransferase activity [10]. While existing research has largely concentrated on clarifying the roles and mechanisms of METTL3 in AKI, renal fibrosis (RF), and CKD, there is a noticeable absence of comprehensive reviews that synthesize and interpret the connections among these topics.

In this review, we thoroughly investigate the relationship between METTL3 and kidney diseases by carefully analyzing the mechanisms through which METTL3 contributes to the pathogenesis, treatment, and therapeutic responses of these renal conditions.

The interplay between METTL3 and AKI

The etiology of AKI generally encompasses ischemia-reperfusion (I/R) events, septic processes, and exposure to nephrotoxins, leading to dysregulated inflammatory responses and apoptosis, which culminate in a sudden decline in renal function [2]. Among these deleterious factors, tubular epithelial cells (TECs) are particularly susceptible and represent the most significantly affected cell type during both the onset and advancement of AKI [9]. METTL3 has been shown to affect various cellular processes by modulating mRNA stability, splicing, translation, and degradation [11]. In AKI, METTL3’s role becomes particularly significant due to its involvement in inflammatory responses, cell death, and subsequent tissue repair mechanisms [12]. Recent studies have highlighted that the dysregulation of METTL3 can lead to aberrant m6A methylation patterns, contributing to the pathogenesis of AKI [8, 13].

METTL3 facilitates the initiation and advancement of AKI

The expression levels of METTL3 are markedly elevated in both murine models and human biopsies of AKI, indicating a strong correlation with renal inflammation and damage through a c-Jun-dependent pathway [10]. Silencing METTL3 reduces renal inflammation and programmed cell death in TECs triggered by tumor necrosis factor-α (TNF-α), Cisplatin, and lipopolysaccharide stimulation, while its overexpression leads to opposite outcomes [10]. Moreover, the conditional knockout of Mettl3 in mouse kidneys alleviates renal dysfunction, injury, and inflammation caused by Cisplatin and I/R [10]. A study has indicated that METTL3 serves a crucial regulatory function in the translation of certain mRNAs characterized by m6A peaks near their stop codons [14]. Furthermore, METTL3 has been found to engage with other mRNA regions, including coding sequences, thereby promoting translation efficiency [15]. For example, TAB3 [TGF-β-activated kinase 1 (MAP3K7) binding protein 3] is a target of METTL3 [10]. Wang et al. [10] reported that METTL3, together with IGF2BP2, enhances TAB3’s stability by binding to its m6A-modified stop codon regions. Notably, METTL3 promotes m6A modification of TAB3, further stabilizing it through IGF2BP2-dependent mechanisms. Both genetic and pharmacological inhibition of METTL3 have demonstrated protective effects against renal injury and inflammation, indicating that targeting the METTL3/TAB3 pathway may offer a promising strategy for the treatment of AKI [10] ( Table 1; Fig. 1).

Table 1 METTL3 facilitates the progression of renal damage from acute phases to fibrotic and chronic stages by differentially modulating specific targets
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Fig. 1
figure 1

Cascades and mechanisms of METTL3 in different kidney diseases. The pathogenesis of AKI includes METTL3-induced mitochondrial impairment, inflammation, TEC apoptosis, and TEC ferroptosis. These events subsequently cause nephrotoxicity and extracellular matrix deposition around MECs, leading to renal parenchymal sclerosis and the formation of renal scar tissue, thereby inducing RF. The progression of RF is further marked by TEC senescence, dysfunction of both TECs and podocytes, as well as MEC proliferation and inflammation, ultimately resulting in CKD associated with obstructive nephropathy, diabetic nephropathy, or hypertensive nephropathy. Methyltransferase-like 3 (METTL3). N6-methyladenosine (m6A). Tubular epithelial cell (TEC). Mesangial cell (MEC). Insulin-like growth factor 2 mRNA binding protein family (IGF2BP). Forkhead box D1 (FOXD1). Kelch-like ECH-associated protein 1 (Keap1). Nuclear factor erythroid 2-related factor 2 (Nrf2). Transforming growth factor-β1 (TGF-β1). Connective tissue growth factor (CTGF). LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Focal adhesion kinase (FAK). YTH N6-methyladenosine RNA binding protein (YTHDF). Putative kinase 1 (PINK1). Nuclear receptor-binding SET domain protein 2 (NSD2). Tissue inhibitor of the metalloproteinase 2(TIMP2). NLR family pyrin domain-containing 3 (NLRP3). Tumor necrosis factor–α (TNF-α). Cellular MYC (c-MYC). Arginine vasopressin receptor 2 (Avpr2)

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Apoptosis, or programmed cell death, is an essential process governed by genetic factors [16]. A recent study has shown that in I/R-induced AKI, METTL3 expression is upregulated [17]. Inhibiting METTL3 results in lower m6A levels and reduced cellular apoptosis. Additionally, m6A-methylated RNA sequencing highlights the significant downregulation of forkhead box D1 (FOXD1), which is crucial for preventing the proliferation of TECs and kidney development, a process reliant on METTL3 methylation [17]. Mitochondrial dysfunction further indicates apoptosis occurrence, as it leads to cell death, tissue damage, and organ failure, particularly in AKI [18]. Research into AKI mechanisms has identified that METTL3 contributes to mitochondrial damage by influencing the stability of the MDM2-p53-LMNB1 pathway [19] (Table 1; Fig. 1). Furthermore, mitochondria generate reactive oxygen species (ROS) during ferroptosis, exacerbating renal cell death in AKI. Reducing METTL3 levels decreases m6A modification on MDM2, which increases p53 and decreases LMNB1, ultimately mitigating both ferroptosis and mitochondrial injury in kidney TECs after AKI [20].

Long non-coding RNAs (lncRNAs) regulate microRNA (miRNA) activity by acting as competing endogenous RNAs (ceRNAs), influencing target gene expression [21]. METTL3-mediated m6A modification of lncRNAs is vital for AKI development. Pan et al. [22] found that reducing METTL3 levels alleviates ischemia-induced AKI by decreasing renal cell apoptosis. Increased levels of lncRNA 121,686 were noted, which enhances apoptosis in mouse renal cells due to I/R. Mechanistically, lncRNA 121,686 functions as a ceRNA, binding miR-328-5p and inhibiting its repression of high-temperature requirement factor A 3 (Htra3). Similarly, the related lncRNA 520,657 also sequesters miR-328-5p, increasing Htra3 expression and promoting I/R-induced apoptosis in human renal cells [22]. Importantly, the expression of both lncRNA 121,686 and lncRNA 520,657 relies on METTL3 through m6A modification [22]. Thus, targeting the METTL3/lncRNA121686/lncRNA520657/miR-328-5p/ Htra3 pathway may offer a potential therapeutic approach for AKI (Table 1; Fig. 1).

In summary, the dysregulation of METTL3 and its impact on m6A methylation patterns underscores the intricate molecular mechanisms driving AKI. One crucial aspect is the modulation of inflammatory cytokine production, which is pivotal in the progression of AKI. METTL3 can influence the expression of key inflammatory mediators, thereby altering the inflammatory milieu within the renal microenvironment. This alteration can either exacerbate or ameliorate the injury, depending on the context and extent of METTL3 activity. Furthermore, the role of METTL3 in cell death pathways, particularly apoptosis and necroptosis, is of paramount importance. By regulating the stability and translation of apoptosis-related mRNAs, METTL3 can dictate the survival or death of TECs under stress conditions. This regulation is not only critical in the initial phase of injury but also in determining the extent of tubular damage and subsequent recovery. In the context of tissue repair, METTL3’s influence extends to the regenerative capacity of TECs. By modulating the expression of genes involved in cell proliferation and differentiation, METTL3 can facilitate the repair and regeneration of damaged renal epithelium. This regenerative aspect is crucial for restoring renal function post-AKI and minimizing long-term renal impairment. Therefore, targeting METTL3 and its downstream m6A methylation pathways presents a promising therapeutic avenue.

METTL3 mediates chemoresistance in AKI

Cisplatin is a powerful chemotherapy drug commonly used to treat malignant solid tumors, but it is primarily excreted by the kidneys, leading to renal damage in about 30% of patients after high doses, which restricts its clinical effectiveness [23, 24]. Research has shown that Cisplatin treatment increases global m6A levels during nephrotoxicity development in AKI, especially involving METTL3 that is significantly unregulated, which might be associated with the elevation of m6A modification in Cis-AKI, contributing to the development of AKI [25]. AKI is marked by increased apoptosis, which worsens renal function [26]. In this context, METTL3 facilitates apoptosis and raises m6A levels in Cisplatin-treated HK2 cells [27]. Similarly, elevated m6A and m6A regulators, including METTL3, have been noted in AKI caused by CdCl2 [28] and Cadmium exposure [29]. However, the exact mechanisms by which METTL3 operates in these scenarios remain unclear and need further exploration.

Colistin is commonly employed for the treatment of drug-resistant infections; however, it is also associated with adverse effects, notably nephrotoxicity, which represents the most prevalent side effect [30]. Oxidative stress plays a pivotal role in the pathogenesis of renal toxicity induced by Colistin, contributing to cellular inflammation and apoptosis [31]. The generation of ROS under oxidative stress conditions further exacerbates cell inflammation, apoptosis, and subsequent development of AKI [32]. Notably, downregulation of METTL3 during Colistin-induced nephrotoxicity is observed; however, overexpression of METTL3 confers protection against oxidative stress, apoptosis, and nephrotoxicity induced by Colistin. Mechanistically, METTL3 interacts with the microprocessor protein DGCR8 to positively modulate the m6A-dependent maturation process of miR-873-5p [33, 34]. Subsequently, miR-873-5p regulates the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to counteract Colistin-induced oxidative stress-mediated ROS production and apoptosis [35]. Under oxidative stress, Nrf2 evades the inhibitory binding of Keap1, thereby activating the antioxidant system (e.g., HO-1), inducing alterations in antioxidant enzymes (such as CAT, SOD, and GSH-Px), and mitigating cellular oxidative damage [35]. Collectively, these findings elucidate the involvement of METTL3 and m6A in Colistin-induced nephrotoxicity while underscoring the significance of METTL3-mediated m6A modification in drug-induced toxicity. Given the absence of appropriate guidelines for reference due to Colistin’s side effects and limited clinical application experience [36], this study provides mechanistic insights into Colistin’s adverse effects, suggesting that targeting either METTL3 or the METTL3-miR-873-5p/Keap1-Nrf2 pathway could alleviate renal toxicity and enhance Colistin’s therapeutic index (Table 1; Fig. 1).

Despite significant advancements in the therapy of AKI, its management remains a formidable challenge due to the dearth of specific targets for early diagnosis and effective treatment of both primary symptoms and subsequent complications. Considering the detrimental role of METTL3 in AKI, targeting METTL3 represents a promising therapeutic strategy for the development of drugs against AKI and enhancement of chemo-resistance in AKI.

The interplay between METTL3 and CKD

Pathogenic factors, such as trauma, infection, inflammation, circulatory disorders, and immune responses, inflict damage upon the kidney and renal cells [37]. Subsequently, a substantial accumulation of abnormal extracellular matrix (ECM) deposits occurs in later stages, progressively leading to sclerosis of the renal parenchyma and formation of scar tissue. Ultimately, this process culminates in complete loss of renal function [38]. Consequently, ECM deposition emerges as a pivotal pathological factor contributing to RF and plays a crucial role in the development and progression of CKD. RF represents an essential pathogenesis underlying almost all CKDs including obstructive nephropathy (ON), diabetic nephropathy (DN), and hypertensive nephropathy (HON) [39, 40]. Moreover, RF serves as a bridge connecting AKI with CKD [41].

METTL3 catalyzes the initiation and advancement of RF towards ON

The mechanism underlying ECM deposition remains elusive; however, it is suggested that m6A modification on RNAs may play a role [42]. For instance, Ni et al. [43] demonstrated hyperactivation of METTL3 and increased overall m6A levels in both the tubular region of fibrotic kidneys and HK-2 cells. Upregulated METTL3 enhances m6A modification on EVL mRNA, leading to improved stability and expression in an IGF2BP2-dependent manner. Consequently, the binding of EVL to Smad7 abolishes the suppressive effect of Smad7 on transforming growth factor-β1 (TGF-β1)/Smad3 signal transduction, thereby promoting RF progression. Therefore, targeting the overactivated METTL3/EVL/m6A axis holds promise for therapeutic interventions against RF. Additionally, the sustained release of profibrotic cytokines, particularly TGF-β, contributes to the development of RF and CKD [44]. Connective tissue growth factor (CTGF) has emerged as an alternative target for antifibrotic therapy in CKD, acting downstream of TGF-β signaling pathways [45]. Sun et al. [46] demonstrated a significant increase in long non-coding RNA AI662270 levels in various RF models, which recruits METTL3 to enhance m6A methylation on CTGF mRNA and subsequently stabilizes CTGF mRNA expression. Consistently, elevated levels of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) have been identified as an RF biomarker in patients with ON [47]. Liu et al. [48] demonstrated the involvement of the MALAT1/miR-145/focal adhesion kinase (FAK) axis in mediating the anti-fibrotic effects of docosahexaenoic acid on a TGF-β1-induced RF and unilateral ureteral obstruction (UUO) mouse model. Additionally, they identified that METTL3 overexpression contributes to m6A modification and upregulation of MALAT1 during RF progression. Another study demonstrated a significant increase in miR-21-5p and m6A modification levels in the UUO model, leading to the activation of the sprouty RTK signaling antagonist 1 (SPRY1)/ERK/NF-kB pathway and confirming the role of miR-21-5p in enhancing inflammation during ON [49]. Importantly, METTL3 also catalyzes m6A modification in UUO mice, promoting miR-21-5p maturation and driving ON development. These findings collectively provide initial evidence supporting the involvement of the METTL3-miR-21-5p-SPRY1/ERK/NF-kB axis in ON pathogenesis, thereby contributing to a deeper understanding of RF (Table 1; Fig. 1).

Aging-related changes significantly contribute to the heightened vulnerability to kidney injury [50]. METTL3 possesses the capability to facilitate miRNA maturation, thereby regulating cellular functions associated with aging. During the senescence process of renal TECs, METTL3 expression is suppressed [51]. Mechanistically, METTL3 operates by modulating miR-181a maturation, subsequently leading to inhibition of NF-κB and IL-1α expression and inactivation of the NF-κB pathway. Consequently, based on these findings, it can be hypothesized that targeting METTL3 may offer a rational approach to rescuing TEC senescence. However, further investigations are warranted to elucidate the precise underlying mechanism for this phenomenon (Table 1; Fig. 1).

METTL3 initiates and facilitates the advancement of RF leading to DN

DN, one of the most prevalent complications in patients diagnosed with diabetes and the primary cause of CKD, is characterized by enhanced ECM formation and foot process effacement [52, 53]. The pathological features of DN encompass a range of structural and functional alterations in kidneys, including glomerular and tubular hypertrophy, expansion of mesangial matrix, accumulation of ECM, as well as dysfunction in TECs and podocytes [54]. Current treatment approaches for DN are still limited to regulating hyperglycemia, lipids, and blood pressure; however, they lack precision and efficacy [55, 56]. Therefore, comprehending the molecular-level pathogenesis mechanism of DN would facilitate the exploration of targeted therapies for this disease.

The study indicated that METTL3 is significantly upregulated in DN podocyte cell lines compared with cells cultured in normal glucose [57]. Wang et al. [58] demonstrated that METTL3 contributes to DN progression by mediating m6A modification on the mRNA of putative kinase 1 (PINK1) that is recognized by YTHDF2 and enhances PINK1 expression. PINK1 is a key regulatory protein of mitophagy. The upregulated level of PINK1 subsequently promotes TEC death and inflammation via regulating mitochondrial damage, finally triggering DN progression. In contrast, Tang et al. [59] demonstrated that the expression of METTL3 in patients with DN is significantly downregulated. METTL3 functions by mediating m6A modification on the mRNA of nuclear receptor-binding SET domain protein 2 (NSD2), stabilizing NSD2 in an YTHDF1-dependent manner. NSD2 is a histone methyltransferase that can control insulin secretion and glucose concentration [60, 61]. Specifically, the decreased expression of NSD2 in patients with DN is found to inhibit the activity of insulin and enhance the blood glucose concentration, subsequently resulting in RF and injury [59]. These findings suggest that the abnormally suppressed expression of NSD2 shows a strong link to the onset and development of DN, and METTL3 is a key regulator for NSD2 expression. Collectively, these findings hint to us that whether METTL3 functions to regulate miRNA mature or ceRNA network of lncRNA, or directly regulating mRNAs, it always acts as the central regulator of these genes that are strongly associated with the onset and development of ND. Therefore, targeting METTL3 serves as a potential method for ND treatment (Table 1; Fig. 1).

The podocytes, as highly specialized glomerular epithelial cells, play a crucial role in upholding the integrity of the glomerular filtration barrier [62]. METTL3 expression is elevated in podocytes of renal biopsy samples from patients with DN, thereby promoting inflammation and apoptosis in these cells [63]. Increased levels of METTL3 are positively associated with 24-hour urinary albumin excretion and creatinine, while being negatively correlated with glomerular filtration rate, suggesting that METTL3 could serve as an indicator of disease severity in patients with DN [63]. Mechanistically, METTL3 mediates m6A modification on the mRNA of tissue inhibitor of metalloproteinase 2 (TIMP2) in an IGF2BP2-dependent manner, activating the Notch signaling pathway and subsequent pro-inflammatory and pro-apoptotic effects. TIMP2, a member of the TIMP family, emerges as an early biomarker for predicting DN due to its role as a key downstream target regulated by METTL3 [63]. Furthermore, the critical role of TIMP2 in the IGF2BP2-dependent pathway highlights its significance beyond mere biomarker identification. By mediating m6A modification through METTL3, TIMP2’s regulatory capacity extends to influencing ECM remodeling and cellular apoptosis, both crucial in the pathogenesis of DN [64]. The modulation of TIMP2 expression via METTL3 thus presents a dual opportunity: it not only serves as an early indicator of disease progression but also as a potential therapeutic target to mitigate the adverse effects of DN. In addition to TIMP2’s involvement, the enhancement of the Notch signaling pathway by METTL3-induced m6A modifications leads to an upregulation of various pro-inflammatory factors. This cascade includes increased expression of cytokines such as TNF-α, IL-6, and IL-1β, which are pivotal in exacerbating inflammatory responses within renal tissues [65]. These cytokines contribute to a pro-inflammatory milieu that perpetuates tissue injury and fibrosis, underscoring the necessity of targeted strategies to curb inflammation early in the disease process. Moreover, the pro-apoptotic effects mediated through this pathway further complicate the progression of DN. These findings underscore the potential therapeutic strategy targeting or modulating METTL3 for treating DN. Additionally, Liu et al. [66] have demonstrated that flavones derived from Abelmoschus manihot can mitigate pyroptosis and podocyte damage in DN by modulating METTL3-mediated m6A modification. This modulation regulates the activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome as well as PTEN/PI3K/AKT signaling pathways. Furthermore, circular RNAs (circRNAs) are a distinct class of non-coding RNAs that play significant roles in DN [67]. Renal biopsy samples from patients with DN exhibit decreased levels of circ-0,000,953, which is strongly associated with renal function impairment [68]. Circ-0,000,953 directly interacts with mir665-3p-Atg4b to execute its roles. Suppression of mir665-3p or upregulation of Atg4b restores podocyte autophagy both in vitro and in vivo [68]. Bioinformatics prediction suggests that the downregulation of circ-0,000,953 is linked to METTL3-mediated m6A methylation. METTL3 modulates the expression and methylation status of circ-0,000,953 through the assistance of YTHDF2. In conclusion, circ-0,000,953 regulates podocyte autophagy in DN by targeting the mir665-3p-Atg4b axis. Therefore, METTL3-mediated m6A modification on circ-0,000,953 holds promise as a potential biomarker for the prevention and treatment of DN (Table 1; Fig. 1).

METTL3 molecular aspects in CKDs

Under the influence of extracellular inflammation and hyperglycemia, mesangial cells (MECs) undergo abnormal proliferation and stimulate excessive secretion of ECM as well as intracellular protein synthesis [69, 70]. The aberrant proliferation and inflammatory response of MECs are pivotal pathological characteristics observed in human renal diseases such as chronic glomerulonephritis (CGN) [71] and lupus nephritis (LN) [72]. CGN and LN belong to the category of glomerular autoimmune diseases in CKD, which are characterized by MEC proliferation, ECM accumulation, and infiltration of inflammatory cells [73,74,75]. Liu et al. [76] demonstrated that METTL3 plays a pivotal role in the initiation and progression of CGN by facilitating the secretion of inflammatory cytokines, including IL-6 and TNF-α while impeding cell proliferation and cycle progression. Additionally, the upregulation of METTL3 expression in LN suggests its intimate association with the immune microenvironment [77]. Nevertheless, the precise underlying mechanisms through which METTL3 exerts its functions in CGN and LN remain elusive, necessitating further investigation (Table 1; Fig. 1).

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disorder, characterized by progressive enlargement of cysts [78]. METTL3 and m6A levels are significantly elevated in both murine and human ADPKD samples [79]. Kidney-specific overexpression of METTL3 leads to tubular cyst formation in three orthologous ADPKD mouse models; however, this growth is attenuated upon knockdown of METTL3 expression [79]. Intriguingly, the ADPKD mouse model exhibits elevated methionine and S-adenosylmethionine levels, which induce METTL3 expression and exacerbate ex vivo cyst growth. Conversely, dietary restriction of methionine mitigates this pathology. Furthermore, METTL3 activates c-MYC and cAMP pathways, promoting cystogenesis through enhanced translation of c-MYC and arginine vasopressin receptor 2 (Avpr2) mRNA [79]. Thus, c-MYC and Avpr2 represent direct targets of METTL3 in ADPKD pathogenesis. These findings underscore the deleterious role played by METTL3 in triggering diverse renal diseases (Table 1; Fig. 1).

In summary, METTL3 emerges as a risk gene in CKD, exerting its influence through the regulation of ECM deposition, TEC senescence, death, inflammation, mitochondrial damage, diabetic podocyte inflammation, apoptosis, and pyroptosis. Consequently, targeting METTL3 represents a promising therapeutic approach for managing CKD and enhancing chemo-resistance against this condition.

Discussion

This review posits that METTL3 facilitates renal injury, spanning from AKI to RF, ultimately progressing to CKD through the mediation of m6A modification on various target RNAs, such as TAB3, FOXD1, and MDM2, et al. in AKI, EVL, CTGF, and MALAT1, et al. in RF, and TMIP2, NLRP3, and Circ-0,000,953, et al. in CDK. The pathogenic mechanism of METTL3 encompasses mitochondrial dysfunction, inflammatory responses, apoptosis of TECs, and ferroptosis in TECs, which collectively exacerbate nephrotoxicity and ECM deposition around mesenchymal cells. These pathological events lead to renal parenchymal sclerosis and the formation of renal scar tissue, culminating in RF. The further advancement of RF instigates TEC senescence, dysfunction in both TECs and podocytes, alongside proliferation and inflammation in MECs, eventually manifesting in CKD, including ON, DN, and HON.

METTL3’s implication in the diagnosis and treatment of kidney diseases

METTL3 expression is significantly upregulated in various kidney disease models, including CKD, RF, and AKI. Elevated METTL3 levels correlate with increased m6A modifications, which in turn regulate the stability and translation of mRNAs involved in inflammatory and fibrotic pathways. This suggests that METTL3 not only serves as a potential biomarker for early detection but also as a therapeutic target. In clinical settings, the quantification of METTL3 expression in renal biopsies could provide prognostic insights. Patients exhibiting higher METTL3 levels tend to have a poorer prognosis, characterized by accelerated disease progression and reduced response to conventional therapies [80]. Therefore, integrating METTL3 expression analysis into routine diagnostic procedures could enhance the accuracy of prognosis and personalize treatment plans.

Furthermore, exploring therapeutic strategies focused on METTL3 is crucial, as the modulation of METTL3 could unveil novel treatments to alleviate renal injury and hinder the progression to chronic conditions such as CKD [81]. Numerous inhibitors and genetic models targeting METTL3 have been developed and have shown promise in preclinical trials [10, 82]. For instance, STM2457 has emerged as a potent inhibitor of METTL3, demonstrating significant antileukemic activity in preclinical models [82]. This compound specifically targets the catalytic domain of METTL3, thereby impeding its methyltransferase activity and subsequent m6A methylation. Moreover, shRNA and siRNA-mediated knockdown approaches have also been employed to transiently suppress METTL3 expression, thereby allowing researchers to study its effects on gene expression, cell proliferation, and apoptosis [80, 83, 84]. These methodologies have been instrumental in effectively reducing m6A modifications and thereby revealing the pivotal role of METTL3 in attenuating the expression of pro-inflammatory and pro-fibrotic genes. Consequently, METTL3 inhibition could emerge as a novel therapeutic strategy, offering hope for patients with limited treatment options.

To further elucidate the role of METTL3 inhibition, developing small molecule inhibitors that selectively inhibit METTL3 activity presents a promising approach [84]. These inhibitors could obstruct m6A modification on target RNAs, thereby disrupting downstream pathways responsible for mitochondrial impairment, inflammatory responses, apoptosis, and ferroptosis in TECs. By mitigating these adverse processes, METTL3 inhibitors could diminish nephrotoxicity and ECM deposition, ultimately preventing renal parenchymal sclerosis and scar tissue formation. Additionally, gene editing technologies, such as CRISPR/Cas9, offer a viable strategy to target METTL3 [85]. By precisely editing the METTL3 gene, it may be feasible to reduce its expression or alter its function, thereby alleviating its deleterious effects on renal cells. Nonetheless, ensuring the specificity and safety of these gene editing techniques remains a challenge, as off-target effects could result in unintended consequences [85]. Investigating upstream regulators and downstream effectors of METTL3 may reveal supplementary therapeutic targets. Identifying signaling pathways or transcription factors that govern METTL3 expression could provide alternative intervention strategies. Similarly, elucidating specific m6A-modified RNAs implicated in renal injury might uncover novel biomarkers or therapeutic targets that are more accessible or easier to modulate than METTL3 itself. Beyond direct targeting of METTL3, leveraging systems biology approaches to understand the broader network of interactions involving METTL3 could enhance therapeutic strategies. Integrative analyses combining transcriptomics, proteomics, and metabolomics data could furnish a comprehensive view of the molecular landscape influenced by METTL3. This holistic understanding might identify synergistic targets or pathways that can be co-modulated for more effective renal protection.

The successful clinical application of METTL3-targeted therapies requires robust preclinical models that closely mimic human renal disease. Advances in organoid technology and tissue engineering hold promise for creating more physiologically relevant models to assess the efficacy and safety of METTL3 inhibitors or gene editing strategies [86, 87]. Additionally, longitudinal studies in animal models and human cohorts are crucial to evaluate the long-term benefits and potential side effects of these treatments. Stratifying patients based on METTL3 activity or m6A modification patterns could enhance the precision of therapeutic interventions. Biomarker-driven approaches might identify individuals most likely to benefit from METTL3-targeted therapies, maximizing efficacy while minimizing unnecessary treatments. Personalized medicine strategies that integrate genetic, epigenetic, and environmental factors could further refine treatment plans to improve outcomes for patients with renal disease [88]. Therefore, targeting METTL3 stands as a promising frontier in treating renal diseases. By inhibiting METTL3’s activity, modulating its expression, or intervening in its regulatory network, we may be able to prevent the progression of renal injury and the development of CKD. Future research should focus on refining these strategies that modulating the activity and expression of METTL3, ensuring their safety and efficacy, and translating them into clinical practice to benefit patients suffering from renal disorders.

Future perspectives

Although these promising avenues exist, current research has limitations in clarifying the mechanisms behind METTL3-mediated chemo-resistance in AKI, CGN, and LN. Future studies should delve into the specific signaling pathways and molecular mechanisms through which METTL3 imparts chemo-resistance in these conditions. One potential research area could be investigating METTL3’s influence on apoptosis, autophagy, and DNA repair processes, which are crucial for determining cellular responses to chemotherapy. For example, understanding how METTL3 regulates the expression of key genes involved in these pathways could shed light on its role in chemo-resistance. Additionally, examining the interaction between METTL3 and other epigenetic modifiers would be valuable. METTL3 interacts with various proteins to exert its functions, and these interactions might be pivotal in mediating chemo-resistance. Comprehensive proteomic and transcriptomic analyses could identify these interacting partners and elucidate their roles in kidney diseases. Moreover, the heterogeneity of kidney cells and how METTL3 might affect different cell types is another significant consideration. Single-cell RNA sequencing (scRNA-seq) could be employed to dissect the cell-type-specific effects of METTL3 and understand how these contribute to the overall chemo-resistance observed in AKI, CGN, and LN. This approach would also help identify specific cell populations more susceptible to METTL3-mediated modifications [89]. Furthermore, exploring the impact of METTL3 on the tumor microenvironment in kidney diseases could provide additional insights. The microenvironment plays a crucial role in modulating chemo-resistance, and METTL3 might influence the behavior of stromal cells, immune cells, and ECM components [90]. Investigating these aspects could reveal novel therapeutic targets to overcome chemo-resistance.

Additionally, while molecular and cellular studies are essential, the clinical implications of targeting METTL3 should not be overlooked. Preclinical models and clinical trials need to be designed to assess the efficacy and safety of METTL3 inhibitors or modulators in combination with existing chemotherapy regimens. Stratifying patients based on METTL3 expression levels or activity could identify those most likely to benefit from such targeted therapies. It is also important to recognize that chemo-resistance is a multifactorial phenomenon, with METTL3 likely being just one of many contributors. Therefore, a holistic approach that considers multiple pathways and factors is necessary to develop effective strategies to combat chemo-resistance. Integrative analyses combining genomic, epigenomic, proteomic, and metabolomic data could provide a comprehensive understanding of resistance mechanisms and identify potential synergistic targets for therapy. Finally, continuous advancements in technologies such as CRISPR/Cas9 for gene editing and high-throughput screening for drug discovery will facilitate the investigation of METTL3 and other epigenetic regulators. These tools will enable precise manipulation of METTL3 activity and the identification of novel small molecules that can modulate its function, thereby providing new avenues for therapeutic intervention.

Conclusion

In summary, addressing the limitations of current research on METTL3-mediated chemo-resistance in AKI, CGN, and LN requires a multifaceted approach. By delving deeper into the molecular mechanisms, exploring cell-type-specific effects, considering the tumor microenvironment, and integrating clinical considerations, future studies can pave the way for the development of novel and effective therapies to overcome chemo-resistance in kidney diseases. It is imperative to further address these limitations and overcome them. Collectively, this review provides a novel mechanistic understanding of kidney diseases by identifying METTL3 as a potential risk gene and treatment target, thereby promoting its clinical application.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AKI:

Acute kidney injury

CKD:

Chronic kidney disease

m6A:

N6-methyladenosine

METTL3/1:

Methyltransferase-like 3/14

YTHDF:

YTH N6-methyladenosine RNA binding protein

IGF2BP:

Insulin-like growth factor 2 mRNA binding protein family

RF:

Renal fibrosis

I/R:

Ischemia-reperfusion

TECs:

Tubular epithelial cells

TNF-α:

Tumor necrosis factor-α

FOXD1:

Forehead box D1

ROS:

Reactive oxygen species

lncRNA:

Long non-coding RNA

miRNA:

MicroRNA

ceRNA:

Competing endogenous RNA

Htra3:

High-temperature requirement factor A 3

Keap1:

Kelch-like ECH-associated protein 1

Nrf2:

Nuclear factor erythroid 2-related factor 2

ECM:

Extracellular matrix

ON:

Obstructive nephropathy

DN:

Diabetic nephropathy

HON:

Hypertensive nephropathy

TGF-β1:

Transforming growth factor-β1

CTGF:

Connective tissue growth factor

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

FAK:

Focal adhesion kinase

UUO:

Unilateral ureteral obstruction

SPRY1:

Sprouty RTK signaling antagonist 1

PINK1:

Putative kinase 1

NSD2:

Nuclear receptor-binding SET domain protein 2

TIMP2:

Tissue inhibitor of the metalloproteinase 2

NLRP3:

NLR family pyrin domain-containing 3

CircRNAs:

Circular RNAs

MECs:

Mesangial cells

CGN:

Chronic glomerulonephritis

LN:

Lupus nephritis

ADPKD:

Autosomal dominant polycystic kidney disease

c-MYC:

Cellular MYC

Avpr2:

Arginine vasopressin receptor 2

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Acknowledgements

We would like to thank Editage [www.editage.cn] for English language editing.

Funding

This work was supported by Sichuan provincial Science & Technology Program (2022JDKP0040), Sichuan provincial Health Commission Program (21PJ168), Deyang Municipal Science & Technology Program (2021SZZ068), and College-level project of Chengdu University of Traditional Chinese Medicine (YYZX2021026 and YYZX2021020).

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  1. Department of Nephrology, People’s Hospital of Deyang City, Deyang, 618000, China

    Bin Song & Xiaolong Wu

  2. Department of Pediatrics, People’s Hospital of Deyang City, No. 173, Section 1, Taishan North Road, Deyang, Sichuan Province, 618000, China

    Yan Zeng

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BS: Conceptualization and Writing – original draft (lead). XW: Review and editing (equal). YZ: Supervision and Funding acquisition. All authors reviewed the manuscript.

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Song, B., Wu, X. & Zeng, Y. Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases. Hum Genomics 18, 125 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40246-024-00692-8

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Human Genomics

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