Noncoding RNA, friend or foe for nephrolithiasis?

Abstract

Nephrolithiasis is one of the most common diseases in urology, characterized by notable incidence and recurrence rates, leading to significant morbidity and financial burden. Despite its prevalence, the precise mechanisms underlying stone formation remain incompletely understood, thus hindering significant advancements in kidney stone management over the past three decades. Investigating the pivotal biological molecules that govern stone formation has consistently been a challenging and high-priority task. A significant portion of mammalian genomes are transcribed into noncoding RNAs (ncRNAs), which have the ability to modulate gene expression and disease progression. They are thus emerging as a novel target class for diagnostics and pharmaceutical exploration. In recent years, the role of ncRNAs in stone formation has attracted burgeoning attention. They have been found to influence stone formation by regulating ion transportation, oxidative stress injury, inflammation, osteoblastic transformation, autophagy, and pyroptosis. These findings contributes new perspectives on the pathogenesis of nephrolithiasis. To enhance our understanding of the diagnostic and therapeutic potential of nephrolithiasis-associated ncRNAs, we summarized the expression profiles, biological functions, and clinical significance of these ncRNAs in the current review.

Keywords: biomarkers; calcium oxalate; ncRNAs; nephrolithiasis; therapeutic targets.

FIGURE 1

Biogenesis of miRNAs, lncRNAs, and circRNAs. (A) Biogenesis of miRNAs. (B) Biogenesis of circRNAs. (C) Biogenesis of lncRNAs. LncRNAs can be classified into signaling, decoying, scaffolding, and guiding lncRNAs according to their functions. EciRNA, exonic circRNA; CiRNA, circular intronic RNA; EIciRNA, exon-intron circRNA; RBP, RNA binding protein; AGO2, argonaute 2; NXF1, nuclear RNA export factor 1; RISC, RNA-induced silencing complex. This figure was created with BioRender.com.

FIGURE 2

Current strategies for conducting ncRNA expression profiling studies related to kidney stones. PCR: polymerase chain reaction. LncRNAs, long noncoding RNAs; MiRNAs, microRNAs; CircRNAs, circular RNAs. This figure was created with BioRender.com.

FIGURE 3

ncRNAs regulate ion transportation, oxidative stress injury, inflammation, and osteogenic transformation during stone formation. (A) Roles of ncRNAs in urinary ion transportation. (B) Roles of ncRNAs in oxidative stress. (C) Roles of ncRNAs in inflammation. (D) Roles of ncRNAs in osteogenic transformation. AhR, aryl hydrocarbon receptor; AR, androgen receptor; BMP2, bone morphogenetic protein 2; CSF-1, macrophage colony-stimulating factor 1; EGR1, early growth response protein 1; HIF-1α, Hypoxia-inducible factor 1-α; HMGB1, high mobility group protein B1; IRF1, interferon regulatory factor-1; MCP-1, monocyte chemotactic protein 1; MGP, matrix Gla protein; MSX2, homeobox protein MSX-2; NLRP3, NACHT, LRR and PYD domain-containing protein 3; Nrf2, nuclear factor erythroid 2-related 2; OCN, osteocalcin; OPN, osteopontin; RISC, RNA-induced silencing complex; ROS, reactive oxygen species; RUNX2, runt-related transcription factor 2; SIRT1, NAD-dependent protein deacetylase sirtuin-1; Slc13a2, solute carrier family 13 member 2; Slc26a6, solute carrier family 26 member 6; TLR4, toll-like receptor 4; ATG5, autophagy protein 5; TRPV5, transient receptor potential cation channel subfamily V member 5; UMOD, uromodulin; VDR, vitamin D receptor; FoxO1, forkhead box protein O1; MIF, macrophage migration inhibitory factor; Calcr, calcitonin receptor. This figure was created with BioRender.com.