Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion

Abstract

ObjectivesThe progressive impairment of β-cell function results in prolonged deterioration in patients with type 2 diabetes mellitus (T2DM). Interestingly, the finding on pancreatitis secondary to renal injury suggests that potential communication exists between kidney and pancreas. Therefore, we aimed to investigate cell division cycle 42 (Cdc42)-mediated podocyte apoptosis and its effect on insulin secretion in islet β-cells.MethodsType 2 diabetic nephropathy mouse models were established to identify the expression of Cdc42 in podocytes by immunohistochemistry. An in vitro co-culture of mouse podocyte MPC5 and β-TC6 cells was preliminarily established. Subsequently, podocyte apoptosis induced by high glucose and Cdc42 was detected by TUNEL staining and western blotting. In addition, the JNK pathway was examined to determine the mechanism of apoptosis in MPC5 cells. Finally, insulin secretion and expression in β-TC6 cells as well as malondialdehyde (MDA) and superoxide dismutase (SOD) levels in both cell types were examined after the regulation of Cdc42 in MPC5 cells.ResultsCdc42 was highly expressed in the podocytes of diabetic nephropathy mice. Exposure to 25 mM glucose for 48 h induced a significant upregulation of Cdc42, Bax, and cleaved caspase-3 as well as a decreased Bcl-2 expression. In addition, marked apoptosis of MPC5 cells was observed compared to normal glucose treatment. After transfection with Cdc42 plasmid, apoptosis of MPC5 cells was enhanced with an increased expression of p-JNK, whereas inhibition of Cdc42 significantly alleviated podocyte apoptosis accompanied by a downregulation of p-JNK. The glucose-stimulated insulin secretion level of β-TC6 cells decreased after the upregulation of Cdc42 in MPC5 cells. Immunofluorescence staining for insulin showed that co-culture with MPC5 cells carrying the Cdc42 plasmid significantly reduced insulin expression, whereas inhibition of Cdc42 in MPC5 cells alleviated the above-mentioned abnormality of β-TC6 cells. The expression of Cdc42 and p-p38 in β-TC6 cells increased following the upregulation of Cdc42 in MPC5 cells; this was concurrent with augmented MDA levels and decreased SOD activity. The opposite result was observed for Cdc42 knockdown in MPC5 cells.ConclusionsCdc42 in podocytes plays a crucial role in insulin secretion by β-cells, which may provide a new therapeutic target to prevent the vicious cycle of β-cell dysfunction in T2DM.

Cell Division Control Protein 42 Facilitates Diabetic Retinopathy Progression by Activating the MEK/ERK Pathway

“…This finding was partly in line with a previous study, which discovers that CDC42 is upregulated under HG in human renal (Li et al 2020). The reason behind this might be that HG could induce cytoskeletal reorganization; meanwhile, CDC42 was a key regulatory of cytoskeletal reorganization, which could reflect the cytoskeletal changes (Jiang et al 2022). Therefore, an increase in CDC42 was observed under the HG condition.…”

“…Cell division control protein 42 (CDC42) is a member of the Rho GTPases family, which has been found to participate in the modulation of diabetic complications and retinal vascular diseases (Huang et al 2019, Uemura andFukushima 2021). According to a study, CDC42 is upregulated under high glucose (HG), which further causes podocyte apoptosis and attenuates β-cell insulin secretion in type 2 diabetic nephropathy mice (Jiang et al 2022). In addition, another study reports that HGinduced CDC42 participates in the change of the number and length of filopodia in podocytes, which is responsible for the pathology of diabetic nephropathy (Shen et (Lavina et al 2018).…”

Mechanism of Bile‐Processed Coptidis Rhizoma to Treat Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus Based on UPLC‐Q‐TOF/MS and Network Pharmacology

“…CDC42 promotes proliferation and migration of cancer cells under high glucose conditions, activates JNK to produce inflammatory factors and affects insulin signaling through the CDC42-MKK4 pathway. [26][27][28] RAC1 is a membrane GTPase that determines the intensity of oxidative stress. RAC1 in a high glucose state can over-activate NADPH oxidase, which in turn causes cellular oxidative stress damage.…”

Serum cell division cycle 42 reflects the development and progression of diabetic nephropathy in patients with diabetes mellitus

“…Furthermore, studies have indicated that CDC42 participates in the incidence and progression of DN ( 17 , 18 ). For example, in a mouse model with DM decreased expression levels and activity of CDC42 leads to podocyte apoptosis and proteinuria ( 17 ).…”

“…For example, in a mouse model with DM decreased expression levels and activity of CDC42 leads to podocyte apoptosis and proteinuria ( 17 ). Another study reported that CDC42 reduction under high glucose inhibits podocyte apoptosis and affects β-cell insulin secretion in a type 2 DM-induced DN mouse model ( 18 ). However, the clinical role of CDC42 for estimating the development and progression of DN in patients with DM is currently unknown.…”