TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

Abstract

Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.

Figure 1

Role of TGF-β1 in kidney. Multiple effects exerted by TGF-β1 on various cells: podocytes, tubular epithelial cells, and inflammatory cells, for example macrophages, leading to their apoptosis, increased extracellular matrix (ECM) production, epithelial-to-mesenchymal transition (EMT), or activation.

Figure 2

Smad family. (a) The family is composed of three groups: regulatory Smads or receptor-regulated Smads (R-Smads), costimulatory or common-partner Smads (C-Smads), and inhibitory Smads (I-Smads). R-Smads are the ligands for BMP, TGF-β, and activin receptors. Co-Smads are responsible for transport of R-Smads to nucleus, whereas I-Smads are negative regulators. (b) The members of each group are characterized by specific domains. R-Smad contains phosphorylation motif, Ser-x-Ser, at the c-terminal region. MH2 domain is present in all members, whereas MH1 domain is not present in I-Smads.

Figure 3

The role of Smad proteins in renal fibrosis. After binding to its receptor, TGFβ1 stimulates Smad-mediated renal fibrosis. The phosphorylated Smad2 and Smad3 bind to Smad4 and form the Smad complex leading to the upregulation of miR-21 and fibrosis development. Of note, miR-21 inhibits Smad7, which under normal conditions acts as a negative regulator of TGF-β1/Smad3 signaling. Smad2 may protect against renal fibrosis through inhibition of Smad3 binding to TGFβRI as well as by blocking Smad3 nuclear translocation.

Figure 4

miR-21 regulation and mode of action. Upon activation, Smad3 is translocated into the nucleus, where it can regulate miR-21 expression. It can occur at the transcriptional level through binding to SBE located in the miR-21 promoter or posttranscriptionally through altering Drosha microprocessor complex, which results in increased processing of pri-miR-21 to pre-miR-21. miR-21 contributes to renal fibrosis by alteration of several metabolic pathways and targeting Smad7 protein, a negative regulator of TGF-β1/Smad3 signaling.