Asparaginyl endopeptidase protects against podocyte injury in diabetic nephropathy through cleaving cofilin-1

Chuntao Lei,Hua Su,Jihong Lin,Mengran Li,Yang Qiu,Hans-Peter Hammes,Linlin Yang,Xingjie Yin,Chun Zhang,Zhe Hao,Zhentao Zhang,Yaru Xie

doi:10.1038/s41419-022-04621-2

Abstract

Podocyte injury and loss are critical events in diabetic nephropathy (DN); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that asparaginyl endopeptidase (AEP) protects against podocyte injury through modulating the dynamics of the cytoskeleton. AEP was highly upregulated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes; however, AEP gene knockout and its compound inhibitor treatment accelerated DN in streptozotocin-induced diabetic mice, whereas specific induction of AEP in glomerular cells attenuated podocyte injury and renal function deterioration. In vitro, elevated AEP was involved in actin cytoskeleton maintenance and anti-apoptosis effects. Mechanistically, we found that AEP directly cleaved the actin-binding protein cofilin-1 after the asparagine 138 (N138) site. The protein levels of endogenous cofilin-1 1-138 fragments were upregulated in diabetic podocytes, consistent with the changes in AEP levels. Importantly, we found that cofilin-1 1-138 fragments were remarkably unphosphorylated than full-length cofilin-1, indicating the enhanced cytoskeleton maintenance activity of cofilin-1 1-138. Then we validated cofilin-1 1-138 could rescue podocytes from cytoskeleton disarrangement and injury in diabetic conditions. Taken together, our data suggest a protective role of elevated AEP in podocyte injury during DN progression through cleaving cofilin-1 to maintain podocyte cytoskeleton dynamics and defend damage.

Highlights

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus and the leading cause of chronic and endstage renal disease (ESRD) worldwide [1]
We found that asparaginyl endopeptidase (AEP) was signifi- Induction of AEP expression in glomeruli attenuated podocyte cantly elevated in the glomerular area, and the increased AEP injury in diabetic kidneys expression partially colocalized with the podocyte marker protein We determined whether transient increased AEP expression Synaptopodin (Fig. 1C)
In the present study, we revealed for the first time an essential role of AEP in maintaining podocyte physiology function

Summary

Introduction

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus and the leading cause of chronic and endstage renal disease (ESRD) worldwide [1]. Podocytes are critical components of the filtration barrier. Various insults under diabetic circumstances can trigger podocyte injury, resulting in the effacement of the foot process and apoptosis, as well as detachment from the basement membrane. These events contribute to the breakdown of the glomerular filtration barrier, thereby resulting in albuminuria [2]. Therapeutic options to prevent or reduce podocyte loss in glomerular diseases, including DN, are currently lacking [5, 6]. A better understanding of the mechanisms underlying podocyte loss is urgently needed to identify potential therapeutic targets

Methods

Results

Conclusion