Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases: an update

Abstract

Epithelial-mesenchymal transition (EMT) is a tightly regulated process by which epithelial cells lose their hallmark epithelial characteristics and gain the features of mesenchymal cells. For podocytes, expression of nephrin, podocin, P-cadherin, and ZO-1 is downregulated, the slit diaphragm (SD) will be altered, and the actin cytoskeleton will be rearranged. Diabetes, especially hyperglycemia, has been demonstrated to incite podocyte EMT through several molecular mechanisms such as TGF-β/Smad classic pathway, Wnt/β-catenin signaling pathway, Integrins/integrin-linked kinase (ILK) signaling pathway, MAPKs signaling pathway, Jagged/Notch signaling pathway, and NF-κB signaling pathway. As one of the most fundamental prerequisites to develop ground-breaking therapeutic options to prevent the development and progression of diabetic kidney disease (DKD), a comprehensive understanding of the molecular mechanisms involved in the pathogenesis of podocyte EMT is compulsory. Therefore, the purpose of this paper is to update the research progress of these underlying signaling pathways and expound the podocyte EMT-related DKDs.

Keywords: Podocyte; diabetic kidney disease; epithelial–mesenchymal transition; hyperglycemia; molecular mechanism.

Figure 1.

EMT process in podocyte. The podocyte comprises three main compartments, the cell body, the major processes, and the foot processes. Each of these segments shares a common actin cytoskeleton. Neighboring foot processes are regularly interdigitated and bridged by a specialized cell–cell junction known as the slit diaphragm. Podocytes can be injured by hyperglycemia through TGF-β/Smad classic pathway and multiple other pathways. Following EMT process, the podocyte foot processes are effaced, which results in a loss of the slit diaphragm. The expression of nephrin, podocin, P-cadherin and ZO-1 is downregulated, the actin cytoskeleton is rearranged and the podocyte is no longer able to restrict urinary protein loss. This EMT process can finally cause podocyte-related diabetic kidney diseases (DKD).

Figure 2.

Molecular mechanisms involved in induction and progression of podocyte EMT caused by hyperglycemia. As can be seen in this figure, high glucose could cause podocyte EMT through multiple signaling pathways like TGF-β/Smad pathway, Wnt pathway, ILK pathway, p38/MAPK pathway, PI3K/AKT pathway, Jagged/Notch pathway and NF-κB pathway, among which TGF-β is the essential cytokine which plays a vital role. The expression of many signaling molecules are disordered, like the downregulation of nephrin, podocin, P-cad, Smad7, ZO-1, and the upregulation of β-catenin, Snail, p-GSK, NICD, N-cad, which leads to podocyte EMT and results in fibrosis, proteinuria and kidney diseases.

Figure 3.

TGF-β/Smad classic pathway. Activated TGF-β first integrates TGF-β receptor type II (TβRII) and TGF-β receptor type I (TβRI) to form ligand receptor complex. This association results in the downstream phosphorylation and activation of Smad2 and Smad3. Phosphorylated Smad2/3 combines with Smad4 to form a Smad complex in cytoplasmic domain and gets nuclear translocation. After translocated into nucleus, the adjusted Smad complex is integrated with EMT-related Smad binding element in gene promoter region to play regulatory roles. Simultaneously, activated TGF-β can also upregulates Smad ubiquitination regulatory factor-2 (Smurf2), an ubiquitin ligase which can degrade TGF-β pathway inhibitors like Smad7, SnoN, Ski, and TGIF. Through this two aspects, activated TGF-β can lead to podocyte EMT independently.

Figure 4.

Cross-link between TGF-β pathway, Wnt pathway, and ILK pathway. This simplified schematic shows major intracellular signaling networks and mediators involved in the regulation of podocyte EMT. Overall, TGF-β is the prototypic inducer and TGF-β/Smad pathway is the essential one of podocyte EMT, whereas the effects of other mediators are often context-dependent, variable, and incomplete. Activated ILK directly phosphorylates several physiologically important downstream effector kinases including Akt and GSK-3β, leading to the stabilization of β-catenin, which indirectly controls the expression of an array of genes that are required for the EMT process. As to Wnt network, upon binding to Wnt receptor, activated Wnt proteins induce a series of downstream signaling events involving Disheveled (Dvl), axin, adenomatosis polyposis coli (APC), casein kinase-1 (CK-1), and GSK-3β, resulting in dephosphorylation of β-catenin. TGF-β, ILK, and Wnt signals are interconnected and converged at the phosphorylation of GSK-3β and activation of β-catenin, which leads to the activation of EMT transcriptional programs. Therefore, β-catenin, to some extent, could function as a master switch that can integrate signal inputs from multiple pathways and control the EMT-related transcriptome.

Figure 5.

Jagged/Notch signaling pathway. Under high glucose condition, Notch receptor is firstly targeted with ligands binding to an adjacent receptor. Then the intramembrane Notch receptor (NICD) is cleaved by metalloproteinases and γ-secretase. The released NICD translocates to the nucleus and interacts with CSL to form a heteromeric complex which acts as an activator of target genes for podocyte EMT and DKD.

Figure 6.

NF-κB signaling pathway. Stimulated by pro-inflammatory cytokines, IκB kinase (IKK) triggers the phosphorylation and degradation of IκBα. Liberated NF-κB then translocates to the nucleus to activate gene expression by recruiting transcriptional coactivators such.