Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy

Abstract

Diabetic nephropathy is a leading cause of end stage renal disease and its occurance is increasing worldwide. The most effective treatment strategy for the condition is intensive treatment to strictly control glycemia and blood pressure using renin-angiotensin system inhibitors. However, a fraction of patients still go on to reach end stage renal disease even under such intensive care. New therapeutic targets for diabetic nephropathy are, therefore, urgently needed. Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis. The accumulation of damaged proteins and organelles is associated with the pathogenesis of diabetic nephropathy. Autophagy in the kidney is activated under some stress conditions, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These and other accumulating findings have led to a hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy. Here, we review recent findings underpinning this hypothesis and discuss the advantages of targeting autophagy for the treatment of diabetic nephropathy.

Keywords: AMP-activated protein kinases; Autophagy; Caloric restriction; Diabetic nephropathy; Mechanistic target of rapamycin complex 1; Podocytes; Sirt1; Tubular cell.

Fig. 1. Nutrient regulation of autophagy. Autohagosome formation is regulated by a number of autophagy-related proteins at multiple steps. Initiation of autophagy via Ulk1 complex is negatively and positively regulated by mammalian target of rapamycin complex 1 (mTORC1)- and 5'-AMP-activated protein kinase (AMPK)-dependent phosphorylation, respectively. Sirt1-dependent deacetylation is also involved in the activation of autophagy. Origin of autophagosome membrane is endoplasmic reticulum (ER) membrane. Autophagosome fuses with lysosome to form autolysosome and is finally degraded by lysosome enzymes. NAD, nicotinamide adenine dinucleotide; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Atg, autophagy-related gene; LC3, light chain 3; Ulk1, unc-51-like kinase 1; PE, phosphatidylethanolamine; FOXO3a, forkhead box O3a.

Fig. 2. Autophagy activity determined using green fluorescent protein light chain 3 (GFP-LC3) transgenic mouse. Autopphagome can be detected as GFP-LC3 dots in tissues of this mouse model. Autophagosomes formation is constitutively observed in podocytes even under ad-libitum condition. In contrast, autophagy can be observed in proximal tubular cells exposed to 48-hour fasting. The white dotted line box indicates the area for each enlarged figure. Blue signal, DAPI stain to visualize nuclei. Red signal, nidogen stain to visualize basement membrane. Green signal, GFP signal indicating LC3 protein.

Fig. 3. Podocytes and proximal tubular cells have basal and stress-responsive autophagy, which is essential to maintain cellular homeostasis. Some pathological situations such as diabetes, obesity, and aging suppresses both basal and stress-responsive autophagy, leading to massive proteinuria and severe tubular cell damage.