title: Hypoxia in the diabetic kidney is independent of advanced glycation end-products.
abstract: Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N(6)-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO(2)) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO(2) and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.
authors.affiliation: Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University, Biomedical Center, Husargatan3, 571, 75123, Uppsala, Sweden. Lina.Nordquist@mcb.uu.se.
authors.forename: Lina
authors.initials: L
authors.lastname: Nordquist
authors.affiliation: Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Liss
authors.affiliation: Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University, Biomedical Center, Husargatan3, 571, 75123, Uppsala, Sweden.
authors.forename: Angelica
authors.initials: A
authors.lastname: Fasching
authors.affiliation: Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University, Biomedical Center, Husargatan3, 571, 75123, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Hansell
authors.affiliation: Division of Integrative Physiology, Departments of Medical Cell Biology, Uppsala University, Biomedical Center, Husargatan3, 571, 75123, Uppsala, Sweden.|Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D048909:Diabetes Complications / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000627:therapeutic use; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D011920:Rats, Inbred WF
chemical_list: D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D019001:Nitric Oxide Synthase; C004479:pimagedine