Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease

Abstract

Proteinuria-induced damage to renal tubular epithelial cells is one of the main causes of diabetic kidney disease (DKD), and the clearance of overloaded albumin by lysosomes is crucial for maintaining the homeostasis of renal tubular epithelial cells. Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking. Melatonin (MLT) is secreted by the pineal gland and can not only regulate circadian rhythms but also maintain lysosomal homeostasis. In this study, we demonstrate the presence of significant lysosomal damage in the renal tubules of DKD patients, which causes autophagy impairment and a concomitant oxidative stress imbalance; however, MLT can upregulate transcription factor EB (TFEB) to improve lysosomal damage and restore the biosynthesis of this organelle. Mechanistically, MLT may protect lysosomes via the upregulation of TFEB and the miR-205-5p-LRP-1 pathway in renal tubules, thus improving autophagy dysfunction and oxidative imbalance in DKD.

1. Introduction

Diabetic kidney disease (DKD) is a microvascular disease caused by diabetes that is associated with significant mortality and disability [1]. Regrettably, few effective DKD treatments currently exist [2]. Thus, the discovery of novel pathophysiological mechanisms and the formulation of novel treatment approaches for DKD are needed.

Urinary albumin is not only the most characteristic clinical manifestation of DKD but also an independent risk factor for its progression [3,4]. Previous studies have shown that prolonged exposure to an excessive amount of albumin can result in the overloading of albumin in renal tubular epithelial cells, which induces inflammatory responses, oxidative stress, and apoptosis [5,6]. In addition, increasing evidence suggests that autophagy can protect renal tubular epithelial cells from damage in various kidney diseases, including DKD [7,8].

As the main degradation system in cells, autophagy plays an important role in adapting to environmental changes, maintaining internal homeostasis, responding to stress and maintaining cellular function [9]. The degradative capacity of autophagy originates in lysosomes; therefore, lysosomes occupy a position at the core of the autophagic process. Although lysosomes are essential for autophagy, lysosomes are mostly neglected in autophagy studies; thus, the means needed to alleviate lysosomal damage are very limited [10]. Several studies have shown that, in DKD, albumin and glucose overload can cause damage to lysosomes in renal tubular epithelial cells and can subsequently promote DKD occurrence and development [11–13]. Liu et al. [14] reported that lysosomal dysfunction throughout the course of DKD represents the primary mechanism underlying the protective potential of autophagy. Moreover, lysosomal repair can activate autophagy and improve kidney homeostasis [15,16]. Therefore, the inhibition of lysosomal damage and depletion can prevent peroxidation, maintain homeostasis in renal tubular epithelial cells, and thereby improve DKD. Nevertheless, the mechanism of lysosomal damage and repair in renal tubules in DKD is still unclear.