Improving the Dysregulation of FoxO1 Activity Is a Potential Therapy for Alleviating Diabetic Kidney Disease.

Yan Wang,Weichun He

doi:10.3389/fphar.2021.630617

Abstract

A substantial proportion of patients with diabetes will develop kidney disease. Diabetic kidney disease (DKD) is one of the most serious complications in diabetic patients and the leading cause of end-stage kidney disease worldwide. Although some mechanisms have been revealed to contribute to the understanding of the pathogenesis of DKD and some drugs currently in use have been shown to be beneficial, prevention and management of DKD remain tricky and challenging. FoxO1 transcriptional factor is a crucial regulator of cellular homeostasis and posttranslational modification is a major mechanism to alter FoxO1 activity. There is increasing evidence that FoxO1 is involved in the regulation of various cellular processes such as stress resistance, autophagy, cell cycle arrest, and apoptosis, thereby playing an important role in the pathogenesis of DKD. Improving the dysregulation of FoxO1 activity by natural compounds, synthetic drugs, or manipulation of gene expression may attenuate renal cell injury and kidney lesion in the cells cultured under a high-glucose environment and in diabetic animal models. The available data imply that FoxO1 may be a potential clinical target for the prevention and treatment of DKD.

Highlights

Diabetic kidney disease (DKD), one of the common complications related to both types of diabetes, occurs in approximately 30–40% of diabetic patients and is the main cause of end-stage renal disease worldwide (Gnudi et al, 2016; Bonner et al, 2020; Chen et al, 2020)
This review summarizes our current perspectives on the regulation of Forkhead box O (FoxO) activity and the physiological functions of FoxO1, highlighting evidence to support the notion that dysregulated FoxO1 activity contributes toward renal parenchymal cell damage in the pathogenesis of DKD
This study suggests that the antioxidative effect mediated by FoxO1 may play a crucial role in attenuating transforming growth factor (TGF)-β-induced ECM production in Mesangial cell (MC) under an HG environment (Guo et al, 2016)

Summary

Introduction

Diabetic kidney disease (DKD), one of the common complications related to both types of diabetes, occurs in approximately 30–40% of diabetic patients and is the main cause of end-stage renal disease worldwide (Gnudi et al, 2016; Bonner et al, 2020; Chen et al, 2020). Li et al reported that upregulation of FoxO1 activity reversed HGdependent downregulation of PTEN-induced putative kinase 1 (PINK1), an important functional protein in mitophagy, which suggests that, through downstream PINK1/Parkin pathway, FoxO1 limits the production of ROS under HG conditions and maintains mitochondrial morphology and stability, playing a crucial role in the protection against mitochondrial dysfunction and podocyte apoptosis (Li et al, 2016; Li et al, 2017).

Results

Conclusion