Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes

Significance Statement Studies suggest that autophagy may be protective in kidney diseases, but understanding how the autophagic process is specifically altered in each disorder is important for applying it therapeutically. On the basis of the observation that autophagy in proximal tubule epithelial cells is mainly regulated by insulin, the authors used diabetic mouse models to investigate whether types 1 and 2 diabetic nephropathy differ in autophagic status. They found distinct patterns of autophagic dysregulation involved in the pathophysiology of types 1 and 2 diabetic nephropathy, with autophagy induction suppressed in the type 2 diabetic kidney (even under starvation) and basal autophagic activity enhanced in the type 1 diabetic kidney (even under fed conditions). They also provide evidence that activated autophagy protects the type 1 diabetic kidney, whereas autophagic suppression jeopardizes the kidney in type 2 diabetes. Background Evidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in each disorder is critically important in working toward therapeutic applications. Methods Using cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy’s role in PTECs in streptozotocin (STZ)-treated type 1 and db / db type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]) on vulnerability to ischemia-reperfusion injury. Results Administering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In db / db mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in db / db mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and db/db mice. Conclusions Autophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.