Impaired autophagy in the proximal tubules is associated with the progression of diabetic nephropathy — ASN Events
  1. Schedule
  2. ADS Basic Poster Discussions - Mechanistic studies of Diabetic Nephropathy
  3. Impaired autophagy in the proximal tubules is associated with the progression of diabetic nephropathy

Impaired autophagy in the proximal tubules is associated with the progression of diabetic nephropathy (#227)

Gavin C Higgins 1 2 , Vicki Bonke 1 3 , Tuong-Vi Nguyen 1 , Sih Min Tan 1 3 , Runa S.J. Lindblom 1 3 , Sally A Penfold 1 , Karly Sourris 1 3 , Portia M Robb 1 , Judy B DeHaan 1 3 , Georg Ramm 1 2 , George Jerums 4 , Alison Skene 5 , Kathryn E White 6 , Rudy W Bilous 7 , Richard J MacIsaac 8 , Elif I Ekinci 4 9 , David A Power 10 , Mark E Cooper 1 3 , Melinda T Coughlan 1 3
  1. Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia
  3. Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria, Australia
  4. Austin Health and the University of Melbourne, Melbourne, Victoria, Australia
  5. Department of Anatomical Pathology, Austin Health, Melbourne, Victoria, Australia
  6. EM Research Services, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
  7. James Cook University Hospital, Middlesbrough, United Kingdom
  8. Department of Endocrinology & Diabetes, St Vincent's Hospital, Melbourne, Victoria, Australia
  9. Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
  10. Department of Nephrology, Austin Health and the University of Melbourne, Melbourne, Victoria, Australia

Aim: To establish if there is an impairment of autophagy activity in the kidney in Diabetic Nephropathy (DN).

Background: Autophagy is the housekeeping mechanism by which cells turnover damaged proteins and organelles to maintain cellular homeostasis.

Methods: Renal injury was followed in the spontaneously diabetic mouse, the Ins2-Akita mouse, by measuring urinary albumin by ELISA and renal histology at 10 and 20 wk of age. Autophagy activity in the renal cortex was monitored by measuring key markers of the autophagy pathway using western immunoblotting and qPCR. Autophagy was also studied in human renal biopsies obtained from patients with DN compared to healthy donor kidneys via immunohistochemistry and by electron microscopy of proximal tubule cells.

Results: Autophagy activity was increased in the kidney of Ins2 Akita mice at 10 weeks of age as seen by an increase in mRNA expression for Atg7 (1.04±0.12 vs 1.41±0.10 AU, n=8, p<0.05), Bnip3 (1.03±0.09 vs 1.58±0.05 AU, n=8, p<0.001) and PINK1 (1.03±0.09 vs 1.26±0.04 AU, n=8, p<0.05). There was evidence of impaired in autophagy at 20 weeks with an increase in p62 accumulation (0.025±0.004 vs 0.064±0.006, n=6, p<0.001). There was an increase in accumulation of p62 inclusion bodies in the renal cortex of patients with DN (0.0010±0.0002 vs 0.0027±0.0006, n=7-17, p<0.02), a decrease in Atg7 expression (14.19±1.50 vs 7.17±0.64, n=3-19, p<0.001) and a decrease in autophagosome formation in the proximal tubules (0.065±0.007 vs 0.039±0.003, n=4-10, p<0.001).

Conclusions: These data demonstrate that autophagy activity is altered in experimental DN which is consistent with changes observed in type 1 diabetic patients. Taken together these results suggest that impaired autophagy may play a key role in the progression of DN.