| First Author | Miyazawa T | Year | 2013 |
| Journal | Kidney Int | Volume | 84 |
| Issue | 6 | Pages | 1176-88 |
| PubMed ID | 23760291 | Mgi Jnum | J:282748 |
| Mgi Id | MGI:6382329 | Doi | 10.1038/ki.2013.214 |
| Citation | Miyazawa T, et al. (2013) Low nitric oxide bioavailability upregulates renal heparin binding EGF-like growth factor expression. Kidney Int 84(6):1176-88 |
| abstractText | Decreased nitric oxide bioavailability has an important role in the initiation and progression of diabetic nephropathy, but the underlying mechanisms remain unclear. Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression levels increased in the kidneys of both endothelial nitric oxide synthase (eNOS)-knockout and eNOS-knockout diabetic (Lepr(db/db)) mice as early as at 8 weeks of age. Further increases in expression were only seen in eNOS-knockout diabetic mice and paralleled the progression of glomerulopathy. HB-EGF expression increased in endothelium, podocytes, and tubular epithelial cells. In cultured glomerular endothelial cells, the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl) ornithine increased HB-EGF protein expression. Administration of L-NAME dramatically increased renal HB-EGF expression and urinary HB-EGF excretion in diabetic mice. On the other hand, replenishing nitric oxide with sodium nitrate in eNOS-knockout diabetic mice reduced urinary HB-EGF excretion and inhibited the progression of diabetic nephropathy. Furthermore, specific deletion of HB-EGF expression in the endothelium attenuated renal injury in diabetic eNOS-knockout mice. Thus, our results suggest that decreased nitric oxide bioavailability leads to increased HB-EGF expression, which may be an important mediator of the resulting progressive diabetic nephropathy in eNOS-knockout diabetic mice. |
