Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions.

Claudio D Gonzalez,Roxana Resnik,Catalina Nicora Santamarina,Maria I Vaccaro,María Paula Carro Negueruela

doi:10.3390/cells10092497

Abstract

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

Highlights

Atg5, an autophagy regulator, results in autophagy inhibition, which causes glomerulosclerosis and damage to the glomerular filtration barrier (GFB). These findings suggest that autophagy plays an important role in preserving the integrity of podocytes and contributes to the maintenance of normal kidney function [53]
Impaired autophagy is involved in the pathophysiology of Diabetic kidney disease (DKD), which increases
Tubules, interstitial tissues, and the vascular renal compartment suffer from the impact of autophagy dysregulation observed in several stages of chronic kidney disease (CKD)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Chronic hyperglycemia may arise from a lack of insulin production (type 1 diabetes mellitus, T1DM) or to an exaggerated resistance to the cellular effects of insulin, accompanied by a decline in insulin production (type 2 diabetes mellitus, T2DM; the most frequent form) This condition is associated with macro-and microvascular complications. Macroautophagy is a multistep process whereby a double-membrane vesicle, called autophagosome, sequesters the cytoplasmic cargo This eventually fuses with lysosomes to form autolysosomes, resulting in cargo degradation [10]. Autophagosome density at any specific cell results from macroautophagy activation and intensity, as well as the rate of the terminal stage processes driving autolysosome formation. Macroautophagy (hereafter referred to as autophagy) dysregulation is the best studied in the pathophysiology of DKD These alterations may be clinically relevant in terms of disease prognosis and response to therapy

Molecular Basis of Autophagy

Autophagy and Kidneys

Podocytes

Some Areas of Uncertainty and Suggestions for Future Research

Findings

Conclusions