IQGAP1 Mediates Angiotensin II-Induced Apoptosis of Podocytes via the ERK1/2 MAPK Signaling Pathway

Abstract

Background/Aims: The mechanism underlying angiotensin II (AngII)-promoted podocyte apoptosis has not been established. IQ domain GTPase-activating protein 1 (IQGAP1) is a scaffolding protein of the mitogen-activated protein kinases (MAPK) signaling pathway, and plays a significant role in apoptosis. The present study evaluates the role of IQGAP1 in AngII-induced podocyte apoptosis. Methods: We randomly assigned 36 male Wistar rats to a normal saline-infused group, an AngII-infused group, or a normal control group, and measured podocyte apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and transmission electron microscopic analysis. In addition, we exposed differentiated mouse podocytes to AngII and then assessed apoptosis by flow cytometry and Hoechst-33258 staining. Expression of IQGAP1 was measured by Western blotting, real-time PCR and immunofluorescence assay in vivo and in vitro. IQGAP1 siRNA and MAPK pathway inhibitors were further introduced to investigate the role of IQGAP1 and MAPK signaling in the process. Coimmunoprecipitation was used to evaluate the interaction between ERK1/2 and IQGAP1. Results: AngII promoted podocyte apoptosis in vivo and in vitro. IQGAP1 had a linear distribution along the capillary loops of glomeruli in vivo, and was in the cellular membrane and cytoplasm of cultured podocytes. AngII stimulated IQGAP1 expression and increased phosphorylation of P38, JNK, and ERK1/2. Knockdown of IQGAP1 with siRNA prevented AngII-induced apoptosis of podocytes and reduced AngII-induced phosphorylation of ERK1/2, but not that of P38, JNK. This was accompanied by a reduced interaction between ERK1/2 and IQGAP1. Conclusion: IQGAP1 contributes to AngII-induced apoptosis of podocytes by interacting with the ERK1/2 signaling protein.

Csk regulates angiotensin II-induced podocyte apoptosis

“…Csk mRNA and protein expression dramatically increased at 2 and 4 weeks after Ang II treatment compared with control rats. Furthermore, nephrin expression was decreased in glomeruli after Ang II infusion, consistent with our previous reports [8,23]. Double immunofluorescence staining revealed that Csk was distributed linearly along the glomerular capillary loops in vivo and colocalized with the specific podocyte marker nephrin.…”

Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models

“…Treatment with FK506 and CsA can block the apoptosis induced by angiotensin II, endothelin-1 and adriamycin1314. MAPK (mitogen-activated protein kinase) signaling pathway plays an important role in podocyte apoptosis161718. It has also been reported that treatment with FK506 inhibits phosphorylation of the JNK and p38 pathways in human rheumatoid fibroblast-like synoviocytes and mouse macrophages in response to IL-1β and LPS treatment1920.…”

Cabin1 localizes in glomerular podocyte and undergoes nuclear translocation during podocyte injury

“…AngII is one of the crucial factors in chronic kidney disease and podocyte injury. 6,7 We found AngII-induced cytoskeleton disruption and nuclear translocation of Cabin1 in cultured podocytes. These results indicated Cabin1 undergone nuclear translocation during podocyte injury.…”

“…1 Recently, a great deal of SD molecules, which relates to podocyte injury have been recognized, including nephrin, podocin, CD2AP, and TRPC6, etc. 2,3 Angiotensin-II (AngII) is an important risk factor in podocyte injury, researchers found it promoted podocyte apoptosis both in vitro and in vivo [4][5][6][7] AngII binds to cell surface G protein-coupled receptors (GPCR), which couple to heterotrimeric G proteins of the Gq/11 family. 8 Gq enhances podocyte apoptosis in a calcineurin (CaN)-dependent fashion, while the activation of CaN could be blocked by CaN inhibitor.…”