Diabetes-Induced DUSP4 Reduction Promotes Podocyte Dysfunction and Progression of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease. Hyperglycemia-induced podocyte dysfunction is a major contributor of renal function impairment in DN. Previous studies showed that activation of mitogen-activated protein kinase (MAPK) in diabetes promotes podocyte dysfunction and cell death. Dual specificity phosphatases (DUSPs) are a family of phosphatases mainly responsible for MAPK inhibition. In this study, we demonstrated that diabetes and high glucose exposure decreased DUSP4 expression in cultured podocytes and glomeruli. Diabetes-induced DUSP4 reduction enhanced p38 and c-Jun N-terminal kinase (JNK) activity and podocyte dysfunction. The overexpression of DUSP4 prevented the activation of p38, JNK, caspase 3/7 activity, and NADPH oxidase 4 expression induced by high glucose level exposure. Deletion of DUSP4 exacerbated albuminuria and increased mesangial expansion and glomerular fibrosis in diabetic mice. These morphological changes were associated with profound podocyte foot process effacement, cell death, and sustained p38 and JNK activation. Moreover, inhibition of protein kinase C-δ prevented DUSP4 expression decline and p38/JNK activation in the podocytes and renal cortex of diabetic mice. Analysis of DUSP4 expression in the renal cortex of patients with diabetes revealed that decreased DUSP4 mRNA expression correlated with reduced estimated glomerular filtration rate (<60 mL/min/1.73 m2). Thus, this study demonstrates that preserving DUSP4 expression could protect against podocyte dysfunction and preserve glomerular function in DN.

GADD45B Promotes Glucose-Induced Renal Tubular Epithelial-Mesenchymal Transition and Apoptosis via the p38 MAPK and JNK Signaling Pathways

“…Moreover, it is widely known that the MAPK pathway serves as a common mediator of kidney injury (Cuarental et al, 2019), including DKD (Wu et al, 2015). Likewise, we observed that p38 MAPK, JNK, and ERK signaling were markedly upregulated in the diabetic kidney and HK-2 cells exposed to HG, which is consistent with the results of other studies (Wu et al, 2015;Chang et al, 2017;Denhez et al, 2019). Additionally, GADD45B ablation reduced the HG-induced activation of the p38 MAPK and JNK pathways, and GADD45B overexpression enhanced p38 MAPK and JNK pathway activation.…”

“…p38 MAPK has been implicated as a critical factor in renal tubular epithelial cell apoptosis in db/ db mice (Wu et al, 2015). Another study showed that dual inhibition of p38 and JNK activity impeded podocyte dysfunction and the progression of DKD (Denhez et al, 2019). Our research group found increased phosphorylation of ERK in kidneys from streptozotocin-induced diabetic rats and cultured podocytes exposed to HG (Chang et al, 2017).…”

Dusp4 Contributes to Anesthesia Neurotoxicity via Mediated Neural Differentiation in Primates

“…Sevoflurane had only effects on JNK phosphorylation in primate (Figures 1E,H). It is consistent with a previous work where induced DUSP4 reduction enhanced c-Jun N-terminal kinase (JNK) activity (Denhez et al, 2019).…”

Catalpol Ameliorates Podocyte Injury by Stabilizing Cytoskeleton and Enhancing Autophagy in Diabetic Nephropathy

“…Albuminuria is the common clinically manifestation of DN that usually develops before the glomerular filtration rate (GFR) impaired and increases the risk of decline of GFR (Molitch et al, 2010), the prevention of albuminuria is therefore a recommendatory therapy in patients with DN (Looker et al, 2019). Podocyte play a key role in the pathogenesis of DN (Denhez et al, 2019). Multiple clinical studies have confirmed that podocyte foot process effacement is found in DN patients, and such podocyte injury is accompanied with abnormal glomerular filtration function (Shankland, 2006;George et al, 2012;Hara et al, 2019).…”