Autophagy Function and Regulation in Kidney Disease

Abstract

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

“…Thus, we recorded reciprocal changes in the levels of autophagy and apoptosis markers. It was demonstrated recently that autophagy can regulate apoptosis following molecular interactions between the key proteins of these processes, including members of Bcl-2 family, autophagy proteins, and caspases [56]. Firstly, beclin-1 can bind to Bcl-2, which results in inhibition of autophagy [56].…”

“…It was demonstrated recently that autophagy can regulate apoptosis following molecular interactions between the key proteins of these processes, including members of Bcl-2 family, autophagy proteins, and caspases [56]. Firstly, beclin-1 can bind to Bcl-2, which results in inhibition of autophagy [56]. Contrary, release of beclin-1 from the complex with Bcl-2 and phosphorylation of beclin-1 or Bcl-2 promote autophagy [27].…”

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

“…In the kidney, basal autophagy flux is essential to maintain cellular homeostasis and renal function. Kidney-specific autophagy-deficient mice revealed evidence of damaged mitochondria, protein aggregates, endoplasmic reticulum stress, podocyte, and proximal tubular cell loss, and progressive impairment of renal function [142]. The role of AMPK in the regulation of the autophagy flux has been extensively investigated in liver, muscle, brain, or adipocytes, whereas only a few studies explore the role of AMPK in renal autophagy [143][144][145][146].…”

Early Diabetes Aggravates Renal Ischemia/reperfusion-induced Acute Kidney Injury 

“…In the healthy kidney, autophagy acts as a quality control system for cellular metabolism and organelle homeostasis. Under pathological conditions, such as renal IR-induced AKI, autophagy is activated but seems to be unable to provide protection from cellular stress [51]; however, the mechanisms are unknown. In this context, we evaluated the same proteins involved in the autophagic ux in the injured kidneys of nondiabetic and diabetic animals with renal IR-induced AKI.…”