MicroRNA-630: A potential guardian against inflammation in diabetic kidney disease

Abstract

In this editorial, we comment on the article by Wu et al published “MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4”. Diabetic kidney disease (DKD) stands as a significant complication occurring from diabetes mellitus, which contributes substantially to the morbidity and mortality rates worldwide. Renal tubular epithelial cell da-mage, often accompanied by inflammatory responses and mesenchymal trans-differentiation, plays a pivotal role in the progression of DKD. Despite extensive research, the intricate molecular mechanisms underlying these processes remain to be determined. Wu et al remarkable work identifies microRNA-630 (miR-630) as an emerging potential regulator of cell migration, apoptosis, and autophagy, prompting investigation into its association with DKD pathogenesis. This study endeavors to elucidate the impact of miR-630 on TEC injury and the inflammatory response in DKD rats. The role of miR-630 in human DKD will be of interest for future studies.

Key Words: Diabetic kidney disease; MicroRNA; MicroRNA-630; Toll-like receptor 4; Inflammation

Core Tip: Wu et al identified microRNA-630 as a promising candidate for the management of diabetic kidney disease, exerting its protective effects through the regulation of toll-like receptor 4-mediated inflammatory pathways. Further research elucidating the precise molecular mechanisms underlying microRNA-630’s actions and its therapeutic potential is warranted, with the ultimate goal of developing targeted interventions to alleviate the burden of diabetic kidney disease and improve patient outcomes.

INTRODUCTION

Diabetes mellitus is a significant global public health challenge with an increasing prevalence and associated morbidity and mortality. Diabetic kidney disease (DKD) is a serious complication of diabetes that significantly affects patients’ quality of life[1]. DKD is characterized by progressive damage to renal tubular epithelial cells (TECs), which serve as fundamental units responsible for orchestrating the reabsorption of crucial solutes and water within the kidney nephrons[2]. This damage occurs through multifaceted mechanisms intricately intertwined with the metabolic dysregulation characteristics of diabetes[3]. In this editorial, we comment on the article by Wu et al[4] published in the recent issue of the World Journal of Diabetes.

THE CULPRIT: RENAL TEC DAMAGE

Glucose and lipid metabolism dysregulation within TECs stemming from hyperglycemia- and insulin resistance-induced metabolic perturbations is a key pathological hallmark of DKD[5]. Elevated glucose levels within TECs trigger reactive oxygen species production, pro-inflammatory pathway activation, and intracellular signaling cascade dysregulation[6]. These metabolic stressors cause cellular dysfunction, impairing the ability of TECs to maintain a proper electrolyte balance and reabsorb essential nutrients[3].

The inflammatory response is a pivotal player in DKD progression. Hyperglycemia-induced oxidative stress and subsequent pro-inflammatory mediator release stimulate immune cell recruitment and activation within the renal interstitium[7]. Macrophages, lymphocytes, and other immune effectors infiltrate the kidney parenchyma and secrete excess cytokines, chemokines, and growth factors, which perpetuate tissue inflammation and injury[8]. This inflammatory microenvironment exacerbates functional TECs and accelerates renal damage progression. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β directly impair TEC function by disrupting cellular signaling pathways involved in ion transport, nutrient reabsorption, and cell survival[9]. Furthermore, they promote apoptosis and fibrosis within the renal tubules, further compromising kidney function[10,11].

THE ROLE OF MICRORNAS IN DKD

MicroRNAs (miRNAs) are pivotal regulators of intricate DKD pathogenesis and govern the diverse molecular me-chanisms underlying renal damage and dysfunction. These small non-coding RNAs exert their influence post-transcriptionally by binding to the 3′ untranslated region of target mRNAs and orchestrating their degradation or translational repression[12]. In DKD, miRNA is dysregulated in various renal cells, including podocytes[13], TECs[14], endothelial cells[15], and mesangial cells[16], where they intricately modulate key processes such as inflammation, fibrosis, apoptosis, and oxidative stress.

Upregulated miRNAs such as miR-21, miR-146a, and miR-192 impair inflammation in DKD by targeting anti-inflammatory or pro-resolving pathways[17], while downregulated miR-29 family members exert anti-inflammatory effects by inhibiting pro-fibrotic gene expression[18]. Renal fibrosis, a hallmark of DKD, is regulated by miRNAs such as miR-21, miR-192, the miR-200 family, and miR-433, which promote fibrosis by modulating extracellular matrix production and remodeling genes, whereas miR-29 family members counteract fibrosis by suppressing collagen and other fibrotic gene expression[19-21]. Additionally, dysregulated miRNAs, including miR-192, miR-200 family, and miR-216a, contribute to apoptosis and impair cell survival in DKD, whereas miR-21 and miR-29 family members exhibit protective effects by inhibiting apoptosis and enhancing cell survival[22]. Moreover, miRNAs play a pivotal role in regulating oxidative stress responses in DKD; miR-21, miR-200 family members, and miR-34a exacerbate oxidative stress by targeting antioxidant defense genes or activating oxidative stress pathways, whereas miR-29 family members exhibit antioxidant properties and protect against oxidative stress-induced renal injury[23,24]. Taken together, miRNA expression dysregulation intricately contributes to DKD pathogenesis by modulating critical molecular pathways involved in inflammation, fibrosis, apoptosis, and oxidative stress. Understanding the role of miRNAs in DKD pathophysiology holds promise for developing potential therapeutic strategies aimed at preventing or treating DKD.

TOLL-LIKE RECEPTOR 4 IN DKD

The toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors that play a critical role in initiating both innate and adaptive immune responses[25]. TLRs are germline-encoded receptors functioning as pathogen recognition receptors and activated by exogenous pathogen-associated molecules and endogenous danger signals[26].

In DKD, TLR4 activation promotes oxidative stress, which is detrimental to disease progression. Conversely, TLR4 blockage reduces oxidative stress and potentially reverses hyperglycemia[27,28]. This activation is mediated by two primary pathways: The MyD88-dependent pathway, triggered at the cell surface and leading to the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β. Here, TLR4 dimerization recruits TIRAP and MyD88 adaptor proteins, which activate IL-1 receptor-associated kinases and ultimately drive the production of these inflammatory mediators via nuclear factor-kappaB and AP-1 transcription factors[29].

THE ROLE OF MIR-630 AND TLR4 IN DKD

Studies suggest that miR-630 might be involved in cellular processes such as migration, apoptosis, and autophagy[30,31]; however, its role in DKD and the underlying mechanisms were unclear before the current investigation. Wu et al[4] used a well-established rat model of streptozotocin-induced DKD, a drug that damages insulin-producing cells. The rats were then divided into groups, and some received treatment to overexpress miR-630. After a set period, various parameters were evaluated to understand how miR-630 overexpression affects DKD course. Initial observations confirmed that miR-630 expression significantly decreased in the DKD rat kidney tissues compared to that in healthy control kidney tissues. These findings suggest that reduced miR-630 levels may be associated with DKD progression.

The researchers then used bioinformatic tools to predict the potential target genes of miR-630 and identified TLR4 as a possible candidate as it plays a crucial role in inflammatory responses. Further investigation using cell cultures confirmed the link between miR-630 and TLR4. MiR-630 overexpression decreased TLR4 expression, suggesting that miR-630 may regulate TLR4 expression and potentially reduce inflammation.

MIR-630 COMBATS INFLAMMATION AND PROTECTS TECS

Interestingly, the level of key inflammatory markers, including TNF-α, IL-1β, and IL-6, were significantly reduced in the miR-630-overexpressed group compared to that in the control group with DKD. Moreover, the expression of E-cadherin protein, a quintessential marker indicating robust TEC health, was preserved in the miR-630-overexpressed rats, which indicates the potential mitigation of TEC injury and dysfunction. Furthermore, the expression of proteins associated with fibrosis also decreased, further emphasizing the protective effects of miR-630. This multifaceted response suggests that miR-630 not only attenuates inflammation, but also protects against fibrotic progression and cellular transformation, potentially delaying DKD pathogenesis.

IN VIVO EVIDENCE STRENGTHENS THE CASE

Subsequent investigations employing an in vivo model provided robust validation of the initial observations. The renal function improved, and inflammatory marker levels significantly reduced in the rats with DKD treated with an miR-630 agonist, indicating substantial kidney inflammation suppression. Moreover, histopathological assessments revealed diminished renal damage in the miR-630 agonist-treated group compared to that in the untreated DKD control cohort.

FUTURE DIRECTIONS: FROM BENCH TO BEDSIDE

Owing to the established role of TLR4 in DKD pathogenesis, researchers are actively exploring therapeutic strategies to regulate its expression. These potential modulators encompass a diverse range of tools, including antibodies[32], small-molecule inhibitors[33,34], peptides[35], miRNAs[36], nanoparticles[37], lipid A analogs[38], and natural product de-rivatives[39], which have been best reviewed by Ain et al[40] and Zaffaroni and Peri[41]. Additionally, anti-inflammatory agents targeting the TLR4 downstream signaling pathway, particularly nuclear factor-kappaB inhibitors, demonstrate promise in alleviating kidney damage[42].

Although existing therapies offer benefits by reducing inflammation and protecting the kidneys, they often lack specificity. The current study highlights miR-630 as a promising therapeutic target specifically for DKD owing to its ability to regulate TLR4, suggesting a novel and targeted approach for this debilitating diabetic complication. However, further research is necessary to elucidate its tissue specificity and the precise mechanisms underlying its effects as well as translate its overexpression into a safe and effective therapeutic strategy for patients with DKD.

CONCLUSION

DKD poses a severe health burden. Damage to TECs through hyperglycemia-induced oxidative stress, inflammation, and metabolic dysregulation underpins DKD progression. miRNAs emerge as key regulatory molecules, modulating various pathogenic processes including inflammation and oxidative stress. Among these, miR-630 shows significant promise by targeting TLR4, thereby mitigating inflammation and protecting TECs from injury. Wu et al’s study underscores miR-630’s therapeutic potential, demonstrating its ability to reduce inflammatory markers and improve renal function in DKD models[4]. The translation of these findings from bench to bedside could herald a new era of targeted therapies for DKD, emphasizing the need for further research to ensure tissue specificity and therapeutic safety. As our understanding of miRNAs and their interactions with molecular pathways deepens, miR-630 stands out as a promising candidate in the quest to alleviate the burden of DKD and enhance patient outcomes.