title: Low nitric oxide bioavailability upregulates renal heparin binding EGF-like growth factor expression.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Fenghua
authors.initials: F
authors.lastname: Zeng
authors.forename: Suwan
authors.initials: S
authors.lastname: Wang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Fan
authors.forename: Huifang
authors.initials: H
authors.lastname: Cheng
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.forename: Aihua
authors.initials: A
authors.lastname: Bian
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse