MicroRNAs in kidney development and disease

Abstract

MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.

Figure 1. Biogenesis of miRNAs.

MiRNA-encoding genes are transcribed by RNA polymerase II into a primary miRNA (pri-miRNA). Next, a complex formed by the RNA-binding protein DGRC8 and the RNase III enzyme Drosha cleaves the pri-miRNA, generating precursor miRNA (pre-miRNA), which is exported into the cytoplasm through exportin 5. Once in the cytoplasm, the Dicer/TRBP complex cleaves the pre-miRNA, releasing mature miRNA. Finally, the mature miRNA is loaded onto the RISC, driving target mRNA recognition through Watson-Crick base pairing, culminating in gene silencing through translational repression or mRNA degradation. DGRC8, DiGeorge syndrome critical region 8; RISC, RNA-induced silencing complex; TRBP, TAR RNA-binding protein. Created with BioRender.com.

Figure 2. Schematic illustration of the stages of metanephric kidney development.

Signals from the ureteric bud trigger condensation of the metanephric mesenchyme to form a cap of nephron progenitors (cap mesenchyme) around the ureteric bud tips. The cap mesenchyme undergoes a mesenchymal-epithelial transition to form renal vesicles, which develop sequentially into comma- and S-shaped bodies. These structures connect to the ureteric bud stalk, which give rises to the collecting duct. Cells in the proximal domain of the S-shaped body differentiate into specialized epithelial cells of the mature renal corpuscle (i.e., podocytes and Bowman’s capsule cells), while cells in the mid- and distal portions differentiate into the tubular segments of nephron (proximal tubules, loops of Henle, and distal tubules). Created with BioRender.com.

Figure 3. Mutations in miRNA-processing genes result in aberrant miRNA expression and Wilms tumorigenesis.

Recurrent mutations in a metal-binding (Mg²⁺) residue of the RNase IIIb domain of DROSHA (E1147K) or in the double-stranded RNA-binding domain of DGRC8 (E518K) disrupt the cleavage of pri-miRNAs into pre-miRNAs. Mutations in XPO5 (encodes exportin 5) prevent pre-miRNA export, which culminates in pre-miRNA accumulation in the nucleus. Frameshift mutations in TARBP2 (encodes TRBP) and mutations affecting the RNase IIIb domain of DICER1 can disrupt the processing of pre-miRNAs into mature miRNAs. In stem and progenitor cells, members of the let-7 miRNA family function as tumor suppressors, and their expression is tightly regulated by the RNA-binding protein Lin28. Lin28A binds to the terminal loop of let-7 precursors and recruits the activity of the terminal uridyl transferases TUT4/7 to produce uridylated pre-let-7, which is subsequently degraded by DIS3L2. Overexpression of LIN28 and mutations in DISL3L2 have been associated with aberrant mature let-7 expression and Wilms tumorigenesis. Created with BioRender.com.