Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease

Ye Feng,Ri-Ning Tang,Bi-Cheng Liu,Hai-Feng Ni,Xin Zhong,Min Wu,Zuo-Lin Li,Bin Wang,Dan Liu,Cui Wang,Li-Ting Wang,Lin-Li Lv,Tao-Tao Tang,Hong Liu

doi:10.1038/s41419-020-2709-4

Ye Feng, Ri-Ning Tang + Show 12 more

Open Access

https://doi.org/10.1038/s41419-020-2709-4

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Abstract

Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.

Highlights

Exosomes are nanosized vesicles released by fusion of an intermediate endocytic compartment, the multivesicular body, with the plasma membrane[1]
We identified that exosome secretion increased significantly via Interferon regulatory factor 1 (IRF-1)/Rab27a in tubular epithelial cells (TECs) as the initial adaptive response to albumin overload, and KIBRA might participated in stabilizing of Rab27a as reported before[29]
We found that Rab27a expression increased exclusively in TECs with albumin exposure which was transcribed by IRF-1

Summary

Introduction

Exosomes are nanosized vesicles released by fusion of an intermediate endocytic compartment, the multivesicular body, with the plasma membrane[1]. As the intracellular interconnected vesicular network, the cross talk between exosome secretion and cellular lysosome degradation to maintain cellular homeostasis remained unclear[4]. Albuminuria, is a common manifestation of kidney injury, and the independent mediator in accelerating kidney disease progression via aggravating tubular epithelial cell (TEC) injury and tubulointerstitial inflammation[5,6,7]. The importance of urinary albumin in disease progression is recognized, the adaptive response of TECs in the presence of excessive albumin remains to be determined. TECs are well adapted as reclaimer of large molecules, such as albumin, that filtered by glomeruli[8]. The filtered albumin is efficiently reabsorbed by TECs via megalin, cubilin or amnionless (AMN)

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