Autophagy in renal tubular injury and repair

Abstract

Autophagy is a fundamental cellular process that maintains normal function and structure of the cell. It can be induced during stress and serves as an adaptive response for cell survival. Normal kidneys have high metabolic demands yet are relatively hypoxic, especially in the medulla and papilla. Injury or ageing aggravates metabolic perturbation and activates autophagy in many types of renal cells. In the kidney, tubular epithelial cells consume the most energy due to active transport mechanisms and therefore are the most susceptible to injuries from hypoxic or low-energy states. This brief review will summarize current understandings of the biological function and molecular regulation of epithelial autophagy during tubular injury and repair.

Keywords: autophagy; kidney; stress response; tubular injury.

Figure 1

Autophagy in health and disease.

Figure 2

Molecular regulation of autophagy. Autophagy is induced following nutrient and/or energy deficiency, which inactivates the autophagy inhibitor mTORC1 and activates the autophagy stimulator AMPK, resulting in activation of the ULK1 complex. Membrane nucleation and elongation are largely due to the conversion of PtdIns3P from PtdIns catalysed by the class III PI3K complex composed of PIK3C3, PIK3R4 and beclin 1 that is associated with Atg14 and AMBRA1 as shown. Downstream to the ULK1 and PI3K complexes is the ubiquitin-like Atg5–Atg12–Atg16 complex that functions to conjugate phosphatidylethanolamine (PE) to LC3 and produces lipidated LC3. Lipidated LC3 incorporated into the autophagosomal membrane plays an important role in cargo recruitments. Mature autophagosomes fuse with lysosomes to form autolysosomes, and the enclosed cargos are degraded by lysosomal hydrolase. mTORC1, mechanistic target of rapamycin complex 1; AMPK, AMP-activated protein kinase; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns, phosphatidylinositol; BCN1, belin 1; AMBRA1, autophagy and beclin 1 regulator 1; PE, phosphatidylethanolamine.

Figure 3

Basal autophagy maintains tubular normal homeostasis and plays a role in physiological ageing and tubular repair. Tubular stress and injury stimulate autophagy for cell survival and tubular repair. Defective autophagy results in more severe injury and incomplete repair of tubules. Furthermore, non-productive repair could possibly accelerate renal ageing.