Autophagy in Chronic Kidney Diseases

Abstract

Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins. Current evidence suggests that autophagy is critical in kidney physiology and homeostasis. In clinical studies, autophagy activations and inhibitions are linked to acute kidney injuries, chronic kidney diseases, diabetic nephropathies, and polycystic kidney diseases. Oxidative stress, inflammation, and mitochondrial dysfunction, which are implicated as important mechanisms underlying many kidney diseases, modulate the autophagy activation and inhibition and lead to cellular recycling dysfunction. Abnormal autophagy function can induce loss of podocytes, damage proximal tubular cells, and glomerulosclerosis. After acute kidney injuries, activated autophagy protects tubular cells from apoptosis and enhances cellular regeneration. Patients with chronic kidney diseases have impaired autophagy that cannot be reversed by hemodialysis. Multiple nephrotoxic medications also alter the autophagy signaling, by which the mechanistic insights of the drugs are revealed, thus providing the unique opportunity to manage the nephrotoxicity of these drugs. In this review, we summarize the current concepts of autophagy and its molecular aspects in different kidney cells pathophysiology. We also discuss the current evidence of autophagy in acute kidney injury, chronic kidney disease, toxic effects of drugs, and aging kidneys. In addition, we examine therapeutic possibilities targeting the autophagy system in kidney diseases.

Keywords: autophagy; inflammation; kidney diseases; mitochondria; oxidative stress.

Figure 1

Schematic overview of the normal autophagy function in the kidney. Multiple steps in autophagy are modulated in kidney diseases, including autophagy initiation, elongation, maturation, fusion, and final degradation and recycling.

Figure 2

(A). Autophagy in glomerular mesangial cells. AGEs: advanced glycation end-products; Akt: also stand for PKB (Protein kinase B); GSK-3β: glycogen synthase kinase-3β; PI3K: Phosphoinositide 3-kinase; ROS: reactive oxygen species; TGF-β1: transforming growth factor-β1; ER stress: endoplasmic reticulum stress; (B). Autophagy in podocytes. PI3K: Phosphoinositide 3-kinase; AMPK: AMP-activated protein kinase Akt: also stand for PKB (Protein kinase B); ROS: reactive oxygen species; ER stress: endoplasmic reticulum stress; (C). Autophagy in proximal tubular cells. IRI: ischemic reperfusion injury; ROS: reactive oxygen species; ER stress: endoplasmic reticulum stress; PI3K: Phosphoinositide 3-kinase; BUN, blood urea nitrogen; sCr, serum creatinine.

Figure 2

(A). Autophagy in glomerular mesangial cells. AGEs: advanced glycation end-products; Akt: also stand for PKB (Protein kinase B); GSK-3β: glycogen synthase kinase-3β; PI3K: Phosphoinositide 3-kinase; ROS: reactive oxygen species; TGF-β1: transforming growth factor-β1; ER stress: endoplasmic reticulum stress; (B). Autophagy in podocytes. PI3K: Phosphoinositide 3-kinase; AMPK: AMP-activated protein kinase Akt: also stand for PKB (Protein kinase B); ROS: reactive oxygen species; ER stress: endoplasmic reticulum stress; (C). Autophagy in proximal tubular cells. IRI: ischemic reperfusion injury; ROS: reactive oxygen species; ER stress: endoplasmic reticulum stress; PI3K: Phosphoinositide 3-kinase; BUN, blood urea nitrogen; sCr, serum creatinine.

Figure 3

Overview of the different medications that regulate autophagy in different steps, including Rapamycin, Adriamycin, Puromycin, 3-methyladenine and Chloroquine.

Figure 4

Diagram depicting the roles of autophagy in various chronic kidney disease. DN: diabetic nephropathy; LN: lupus nephropathy; APCKD: adult polycystic kidney disease.