IL‐6 increases podocyte motility via MLC‐mediated focal adhesion impairment and cytoskeleton disassembly

Abstract

The disturbance of podocyte motility is an essential pathogenic mechanisms of foot process effacement during proteinuric diseases, and myosin light chain (MLC) is a pivotal component in regulating the motility of podocytes. Inflammatory cytokine interleukin-6 (IL-6) has been reported to induce podocyte abnormalities by various mechanisms, however, whether aberrant cell motility contributes to the IL-6-induced podocyte injury remains unknown. Here, by wound healing, transwell, and cell migration assays, we confirmed that IL-6 accelerates the motility of podocyte. Simultaneously, the phosphorylation of MLC is elevated along with perturbed focal adhesion (FAs) and cytoskeleton. Next, via genetic and pharmacologic interruption of MLC or its phosphorylation we revealed that the activation of MLC is implicated in IL-6-mediated podocyte hypermotility as well as the disassembly of FAs and F-actin. By using stattic, an inhibitor for STAT3 phosphorylation, we uncovered that STAT3 activation is the upstream event for MLC phosphorylation and the following aberrant motility of podocytes. Additionally, we found that calcitriol markedly attenuates podocyte hypermotility via blocking STAT3-MLC. In conclusion, our study demonstrated that IL-6 interrupts FAs dynamic, cytoskeleton organization, and eventually leads to podocyte hypermotility via STAT3/MLC, whereas calcitriol exerts its protective role by inhibiting this pathway. These findings enrich the mechanisms accounting for IL-6-mediated podocyte injury from the standpoint of cell motility and provide a novel therapeutic target for podocyte disorders.

Dietary cysteamine hydrochloride protects against oxidation, inflammation, and mucosal barrier disruption of broiler chickens challenged with Clostridium perfringens

“…Moreover, the thiol group contributes not only to the cellular glutathione level but also to the component of microtubules and tubulin polymerization (Kuriyama and Sakai, 1974), and intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells (Perez et al, 2017). The information about the effect of CSH on cytoskeleton is unavailable, but the tunability of cytoskeleton by N-acetylcystein or other bioactive materials (Ding et al, 2000;Baumgarten et al, 2017;Imai-Sumida et al, 2017;He et al, 2018) indirectly supported the present study, and its mechanistic signaling pathway will be an interesting topic for the future study.…”

“…Perturbing the cellular redox status by depleting intracellular glutathione provoked disruption of microfilaments in human fibroblasts (Kletsas et al, 1998). The cytoskeleton can be regulated by exogenous chemical or bioactive materials (Baumgarten et al, 2017;Imai-Sumida et al, 2017;He et al, 2018), but little is known about the effect of dietary factors or nutraceuticals on the cytoskeleton in farm animals.…”

Regulation of the Actin Cytoskeleton in Podocytes

“…Podocytes express interleukin-6 (IL-6) as well as the IL-6 receptor and can secrete and directly respond to IL-6 in response to proinflammatory stimuli [ 201 , 202 , 203 ]. Treatment of cultured podocytes with IL-6 has been shown to increase podocyte motility via signal transducer and activator of transcription (STAT3)-induced phosphorylation of myosin light chain, leading to decreased stress fiber formation and decreased focal adhesion size [ 204 ].…”

Exploring protective effect of Glycine tabacina aqueous extract against nephrotic syndrome by network pharmacology and experimental verification

“…NOS2 and NOS3, separately encoded the inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), are involved in the synthesis of the nitric oxide (NO) and considered as a significant nephroprotective factor [ 59 ]. Interleukin, the multifunctional inflammatory cytokines are closely associated with various renal diseases and the injury of kidney residential cells, such as IL-6, CXCL8, IL-1β, IL-2 and IL-4 [ 60 – 64 ]. TNF-α, an important regulatory factor, which can promote the production of IL-6, IL-1β, and other cytokines, participates in inflammation, oxidative stress and damage in various renal diseases [ 65 ].…”