Inhibition of the epidermal growth factor receptor preserves podocytes and attenuates albuminuria in experimental diabetic nephropathy

Authors

  • ANDREW ADVANI,

    Corresponding author
    1. Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
      Dr Andrew Advani, 6-151 61 Queen St. East, St. Michael's Hospital, Toronto, ON, Canada, M5C 2T2. Email: advania@smh.ca; Dr Darren J Kelly, Department of Medicine, St. Vincent's Hospital, Level 4 Clinical Sciences Building, 29 Regent Street, Fitzroy, Victoria 3065, Australia. Email: dkelly@medstv.unimelb.edu.au
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    • These authors contributed equally to this work.

    • A.A., R.E.G. and D.J.K. have received research funding and/or honoraria from Novartis Pharmaceuticals, the manufacturer of PKI 166, the compound used in this study.

  • KATHRYN J WIGGINS,

    1. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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    • These authors contributed equally to this work.

  • ALISON J COX,

    1. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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  • YUAN ZHANG,

    1. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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  • RICHARD E GILBERT,

    1. Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
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    • A.A., R.E.G. and D.J.K. have received research funding and/or honoraria from Novartis Pharmaceuticals, the manufacturer of PKI 166, the compound used in this study.

  • DARREN J KELLY

    1. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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    • A.A., R.E.G. and D.J.K. have received research funding and/or honoraria from Novartis Pharmaceuticals, the manufacturer of PKI 166, the compound used in this study.


Dr Andrew Advani, 6-151 61 Queen St. East, St. Michael's Hospital, Toronto, ON, Canada, M5C 2T2. Email: advania@smh.ca; Dr Darren J Kelly, Department of Medicine, St. Vincent's Hospital, Level 4 Clinical Sciences Building, 29 Regent Street, Fitzroy, Victoria 3065, Australia. Email: dkelly@medstv.unimelb.edu.au

ABSTRACT:

Aim:  Early renal enlargement may predict the future development of nephropathy in patients with diabetes. The epidermal growth factor (EGF)-EGF receptor (EGFR) system plays a pivotal role in mediating renal hypertrophy, where it may act to regulate cell growth and proliferation and also to mediate the actions of angiotensin II through transactivation of the EGFR. In the present study we sought to investigate the effects of long-term inhibition of the EGFR tyrosine kinase in an experimental model of diabetes that is characterized by angiotensin II dependent hypertension.

Methods:  Female heterozygous streptozotocin-diabetic TGR(mRen-2)27 rats were treated with the EGFR inhibitor PKI 166 by daily oral dosing for 16 weeks.

Results:  Treatment of TGR(mRen-2)27 rats with PKI 166 attenuated the increase in kidney size, glomerular hypertrophy and albuminuria that occurred with diabetes. The reduction in albuminuria, with EGFR inhibition in diabetic TGR(mRen-2)27 rats, was associated with preservation of the number of glomerular cells staining positively for the podocyte nuclear marker, WT1. Immunostaining for WT1 inversely correlated with glomerular volume in diabetic rats. In contrast to agents that block the renin-angiotensin system (RAS), EGFR inhibition had no effect on either the quantity of mesangial matrix or the magnitude of tubular injury in diabetic animals.

Conclusion:  These observations indicate that inhibition of the tyrosine kinase activity of the EGFR attenuates kidney and glomerular enlargement in association with podocyte preservation and reduction in albuminuria in diabetes. Accordingly, targeting the EGF-EGFR pathway may represent a therapeutic strategy for patients who continue to progress despite RAS-blockade.

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