Life science
Medicine / Healthcare, Drug development

Developing strategies to treat diabetic kidney disease bytargeting autophagic activity
Department of Nephrology, Graduate School of Medicine
Professor Yoshitaka Isaka

Researchmap https://researchmap.jp/isaka-handai3857

Clinical Fellow Takeshi Yamamoto

Researchmap https://researchmap.jp/tyamamoto-handai3857

Life science

AbstractStudies 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 (PTECs) is mainly regulated by insulin, weused diabetic mouse models to investigate whether types 1 and 2
diabetic nephropathy differ in autophagic status. We 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). We also provide evidence thatactivated autophagy protects the type 1 diabetic kidney, whereas
autophagic suppression jeopardizes the kidney in type 2 diabetes.
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.

▍ Background & Results
Background The prevalence of obesity and obesity-related diseases, including type 2 diabetes, dyslipidemia, and hypertension,is increasing, with the number of patients who develop diabetic
kidney disease (DKD), and end stage renal disease increasing
worldwide. Evidence of a protective role of autophagy in kidneydiseases 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. Results Using cultured 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 inautophagy status and autophagy’s role in PTECs in streptozotocin(STZ)-treated type 1 and db/db type 2 diabetic nephropathy. 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-treatedmice, autophagy was enhanced even under fed conditions but
stagnated under starvation due to lysosomal stress. We foundthat, 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. We also examined the effects of rapamycin (an inhibitor of mTOR) on vulnerability to ischemia-reperfusion
injury. Rapamycin-induced pharmacologic autophagy produced
opposite effects on ischemia-reperfusion injury in STZ-treated anddb/db mice.

▍ Significance of the research and Future perspective
Building on the above findings, we proposed two major types ofautophagic dysregulation; autophagic stagnation and autophagic
numbness. Our studies will ultimately lead to fundamental insights
in understanding, diagnosing, and preventing DKD by modulating
autophagy. Our final goal is to develop and apply a new drug to
DKD patients, which will reduce the number of dialysis patients inthe future.

Type 1 DM nephropathy

Insulin

Autophagic numbness

Increased autophagic activity
Lysosomal stressType 1 DM nephropathy

Worsen by increased burden on
autophagy-lysosome system

Type 2 DM nephropathy

InsulinType 2 DM nephropathy

Rescued by restoring
autophagic activity

Autophagic stagnation

Accumulation of undegraded substrates(i.e. protein aggregates, damaged mitochondria)
Diabetes andkidney disease

Vulnerability to additional stresses that require
increased autophagic activity

CellulardamageOrganelle dysfunctions associated with autophagic
dysregulation

P a t e n t patent pending
Sakai, Shinsuke; Yamamoto, Takeshi; Isaka, Yoshitaka et al. Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes. J Am Soc Nephrol. 2019; 30(6):Tr e a t i s e929-945. doi: 10.1681/ASN.2018100983
URL https://www.med.osaka-u.ac.jp/pub/kid/kid/index.html
K e y w o r d diabetic nephropathy (diabetic kidney disease), autophagic flux, autophagic stagnation, insulin, lysosome