GADD45B mediates podocyte injury in zebrafish by activating the ROS-GADD45B-p38 pathway

Abstract

GADD45 gene has been implicated in cell cycle arrest, cell survival or apoptosis in a cell type specific and context-dependent manner. Members of GADD45 gene family have been found differentially expressed in several podocyte injury models, but their roles in podocytes are unclear. Using an in vivo zebrafish model of inducible podocyte injury that we have previously established, we found that zebrafish orthologs of gadd45b were induced upon the induction of podocyte injury. Podocyte-specific overexpression of zebrafish gadd45b exacerbated edema, proteinuria and foot-process effacement, whereas knockdown of gadd45b by morpholino-oligos in zebrafish larvae ameliorated podocyte injury. We then explored the role of GADD45B induction in podocyte injury using in vitro podocyte culture. We confirmed that GADD45B was significantly upregulated during the early phase of podocyte injury in cultured human podocytes and that podocyte apoptosis induced by TGF-β and puromycin aminonucleoside (PAN) was aggravated by GADD45B overexpression but ameliorated by shRNA-mediated GADD45B knockdown. We also showed that ROS inhibitor NAC suppressed PAN-induced GADD45B expression and subsequent activation of p38 MAPK pathway in podocytes and that inhibition of GADD45B diminished PAN-induced p38 MAPK activation. Taken together, our findings demonstrated that GADD45B has an important role in podocyte injury and may be a therapeutic target for the management of podocyte injury in glomerular diseases.

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…Our study demonstrated that integrin α6β4, another integrin family heterodimer, also activated FAK and induced actin filament rearrangements. Consistent with the results of our investigation, the results of studies involving other cell lines have shown that activated integrin α6β4 can recruit FAK, thereby inducing autophosphorylation at Y397, a critical tyrosine site that plays a role in the activation of downstream effectors, such as p38.P38 has been demonstrated to mediate podocyte injury in various models of renal disease; moreover, p38 inhibition has been shown to protect podocytes from injury in vitro and ameliorate proteinuria in vivo . A recent study showed that the FAK/p38 axis contributed to foot process effacement and proteinuria development in a rat model of short‐term hypercholesterolaemia by modulating podocyte apoptosis and F‐actin reorganization .…”

“…Consistent with the results of our investigation, the results of studies involving other cell lines have shown that activated integrin α6β4 can recruit FAK, thereby inducing autophosphorylation at Y397, 21 a critical tyrosine site that plays a role in the activation of downstream effectors, such as p38.P38 has been demonstrated to mediate podocyte injury in various models of renal disease; moreover, p38 inhibition has been shown to protect podocytes from injury in vitro and ameliorate proteinuria in vivo. 29,53 A recent study showed that the FAK/p38 axis contributed to foot process effacement and proteinuria development in a rat model of short-term hypercholesterolaemia by modulating podocyte apoptosis and F-actin reorganization. 4 Consistent with this finding, the results of our study demonstrated that the FAK/p38 axis plays an important role in ADR-induced podocyte injury and showed that plectin and integrin α6ß4 are the upstream inducers of this axis.…”

Matrine inhibits the progression of prostate cancer by promoting expression of GADD45B

“…If GADD45B inhibits autophagy, it logically promotes apoptosis so that tumor cell growth is inhibited, especially in the system of cultured cells. Previous studies have also shown that GADD45B is a potent tumor suppressor . However, autophagy defects enhances pyroptosis and promotes death of tumor cells as well as host cells surrounding tumor cells so that the survivals of animals will be reduced .…”

Metadherin facilitates podocyte apoptosis in diabetic nephropathy

“…15, 16, 37 In addition, the p38 MAPK pathway was shown to have an important role in podocyte injury. 38, 39 The data obtained in this study showed that the expression of p-p38 is significantly enhanced in the DN glomeruli and HG-induced MPC5 cells, and it is accompanied by the increase in the expression of Bax and cleaved caspase 3. The inhibition of Mtdh led to the suppression of the activation of p38 MAPK pathway following the HG treatment, which suggests a possible link between Mtdh and p38 MAPK activation.…”