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Review
. 2009 Jul;4(7):1255-66.
doi: 10.2215/CJN.00520109.

MicroRNAs and their role in progressive kidney diseases

Mitsuo Kato  1 , Laura Arce, Rama Natarajan
Affiliations
Review

MicroRNAs and their role in progressive kidney diseases

Mitsuo Kato et al. Clin J Am Soc Nephrol. 2009 Jul.

Abstract

MicroRNAs (miRs) are a family of short non-coding RNAs. These endogenously produced factors have been shown to play important roles in gene regulation. The discovery of miRs has greatly expanded our knowledge of gene regulation at the posttranscriptional level. miRs inhibit target gene expression by blocking protein translation or by inducing mRNA degradation and therefore have the potential to modulate physiologic and pathologic processes. The imperative need to determine their cellular targets and disease relevance has sparked an unprecedented explosion of research in the miR field. Recent findings have revealed critical functions for specific miRs in cellular events such as proliferation, differentiation, development, and immune responses and in the regulation of genes relevant to human diseases. Of particular interest to renal researchers are recent reports that key miRs are highly expressed in the kidney and can act as effectors of TGF-beta actions and high glucose in diabetic kidney disease. Moreover, podocyte-specific deletion of Dicer, a key enzyme involved in miR biogenesis, led to proteinuria and severe renal dysfunction in mice. Hence, studies aimed at determining the in vitro and in vivo functions of miRs in the kidney could determine their value as therapeutic targets for progressive renal glomerular and tubular diseases. Translational approaches could be facilitated by the development of effective inhibitors of specific miRs and methods for optimal delivery of anti-miRs to the kidney. The major goal of this review is to highlight key functions of these miRs and their relationships to human diseases, with special emphasis on diabetic kidney disease.

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Figures

Figure 1.
Figure 1.
Biogenesis and mechanism of action of microRNAs (miRs). miR transcripts initially originate as primary miRs that are then processed into precursor miRs, which are further cleaved to result in miR–miR duplexes. The miR duplexes are then unwound, and the mature miR guide strand is loaded into the RNA-induced silencing complex (RISC) complex. miRs in the RISC complex then guide the recognition of target RNAs to induce their downregulation depending on the type of complementarity.
Figure 2.
Figure 2.
miR-dependent mechanisms for TGF-β–induced expression of extracellular matrix (ECM) genes related to the pathogenesis of diabetic nephropathy (DN). The expression of miR-192 is increased in diabetic kidney glomeruli in mouse models along with that of collagen type I-α 2 (Col1a2) and TGF-β expression (47). Col1a2 expression is increased by TGF-β or diabetic conditions via decrease in ZEB2 targeted by miR-192 upregulated by TGF-β in mesangial cells (MCs) (47). Because E-boxes are also present in the upstream genomic regions of the miR-200 family, miR-200 family members might themselves be regulated by ZEB1 and ZEB2 (136,138). miR-192 may initiate signaling from TGF-β also to upregulate the miR-200 family, and then the miR-200 family might amplify or accelerate the signaling by further upregulating themselves via downregulation of E-box repressors (Zeb1/Zeb2). The miR-192–regulated circuit may amplify TGF-β signaling under diabetic conditions. miR-377 has also been shown to induce fibronectin (ECM protein) expression via downregulation of manganese superoxide dismutase (MnSOD) and p21-activated kinase (PAK1) in MCs (48).
Figure 3.
Figure 3.
Treating renal disorders in mouse models by targeting specific miRs in vivo with oligonucleotide (oligo) inhibitors such as locked nucleic acid (LNA)-modified anti-miRs or other chemically modified antagomiRs. Cholesterol-tagged anti-miR oligos (antagomiRs) or LNA-modified oligo anti-miRs could be developed as efficient inhibitors of key disease-related miRs. The chemistry of these oligos can be engineered for optimal renal cell targeting, accumulation, and miR inhibition in vivo. Both type 1 and type 2 diabetic mice could be tested by injecting them with specific miR inhibitors or control oligos and examining whether they can prevent or delay key features of DN. Such studies will determine whether the increased rates of DN in the diabetic mice can be attributed at least in part to the aberrant expression of the specific miR being targeted.
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