NDT Advance Access originally published online on August 8, 2007
Nephrology Dialysis Transplantation 2007 22(12):3442-3450; doi:10.1093/ndt/gfm503
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Bone morphogenetic protein-7 delays podocyte injury due to high glucose
1Department of Pediatrics, 2Department of Pathology & Immunology, 3Department of Medicine, 4Department of Cell Biology and 5Department of Anesthesiology, Washington University, St Louis, MO, USA
Correspondence to: Helen Liapis, MD, Department of Pathology & Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8118, Saint Louis, MO 63110-1093, USA. Email: liapis{at}path.wustl.edu
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Abstract |
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Background. The molecular pathogenesis of diabetic glomerulosclerosis remains unknown, but recent studies suggest that podocyte damage may play a role. Bone morphogenetic protein 7 (BMP-7) is physiologically expressed in podocytes and tubular epithelial cells. Our previous studies show that BMP-7 reverses glomerular and tubulointerstitial damage in diabetic rats, but there is little known about possible effects of BMP-7 on podocytes. We postulate that high glucose may injure the podocyte by altering structural proteins such as synaptopodin and podocin. This study investigates the effect of high glucose on mouse podocytes, expression of synaptopodin and podocin under normal and high glucose and the treatment effect of BMP-7 on these molecules. Human diabetic glomeruli are studied in parallel.
Methods. Conditionally immortalized mouse podocytes were exposed to media containing normal (NG) or high (HG) glucose for 2 weeks. Synaptopodin, podocin and BMP-7 gene transcription and protein were assayed with real-time PCR, Western blot or immunohistochemistry, respectively. Synaptopodin and podocin mRNA and protein was evaluated using podocytes incubated in HG for 1 week, in the presence of low (10 ng/ml) and high (300 ng/ml) dose recombinant BMP-7 (rhBMP-7). Human diabetic glomeruli were excised from renal biopsies by laser capture micro-dissection (LCM) and endogenous BMP7 and synaptopodin and podocin were determined by RT-PCR and/or immunohistochemistry.
Results. Culture of podocytes in HG decreases synaptopodin, podocin and BMP-7 transcription and protein synthesis compared to NG. Treatment with rhBMP-7 restores synaptopodin and podocin mRNA and protein. Decreased BMP-7 and synaptopodin is also observed in human diabetic glomeruli both at the transcription and protein level.
Conclusions. BMP-7 may confer resistance to hyperglycaemic injury via synaptopodin and podocin suggesting novel BMP7 therapies for diabetic glomerulosclerosis.
Keywords: BMP-7; high glucose; human; mouse; laser capture microdissection; podocyte
Received for publication: 2. 4.07
Accepted in revised form: 3. 7.07
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