Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model.
BACKGROUND
Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated.


METHODS
Cobalt chloride was given to hypertensive, type 2 diabetic rats with nephropathy (SHR/NDmcr-cp). Treatment was initiated at the age of 13 weeks and continued for 26 weeks.


RESULTS
Cobalt did not correct hypertension and metabolic abnormalities (obesity, hyperglycaemia and hyperlipidaemia) but reduced proteinuria as well as histological kidney injury. Cobalt upregulated renal HIF-1alpha and HIF-2alpha expression and increased the expression of HIF-regulated genes, including erythropoietin, vascular endothelial growth factor and heme oxygenase-1. The renal expression of transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) was significantly reduced by cobalt. The renal expression of NADPH oxidase, a marker of oxidative stress, and the renal content of pentosidine, a marker of advanced glycation, were also significantly reduced by cobalt.


CONCLUSIONS
Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.
Ohtomo
Shuichi
S
Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Nangaku
Masaomi
M
Izuhara
Yuko
Y
Takizawa
Shunya
S
Strihou
Charles van Ypersele de
Cv
Miyata
Toshio
T
D000818:Animals; D016587:Antimutagenic Agents / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003035:Cobalt / Q000627:therapeutic use*; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018450:Disease Progression; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D016587:Antimutagenic Agents; D001120:Arginine; D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D055513:Connective Tissue Growth Factor; D017127:Glycation End Products, Advanced; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008239:Lysine; D019255:NADPH Oxidases; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000099162:Endothelial PAS Domain-Containing Protein 1; C526316:CCN2 protein, rat; C497444:Hif1a protein, rat; C062187:pentosidine; C018021:cobaltous chloride