Kidney expression of glutathione peroxidase-1 is not protective against streptozotocin-induced diabetic nephropathy.
In many diseases, including progressive renal disorders, tissue injury and pathological intracellular signaling events are dependent on oxidative stress. Glutathione peroxidase-1 (Gpx1) is an antioxidant enzyme that is highly expressed in the kidney and removes peroxides and peroxynitrite that can cause renal damage. Therefore, we examined whether this abundant renal antioxidant enzyme limits renal damage during the development of type 1 diabetic nephropathy. Wild-type (Gpx1+/+) and deficient (Gpx1-/-) mice were made diabetic by intraperitoneal injection of streptozotocin (100 mg/kg) on 2 consecutive days. Diabetic Gpx1+/+ and -/- mice with equivalent blood glucose levels (23 +/- 4 mM) were selected and examined after 4 mo of diabetes. Compared with normal mice, diabetic Gpx1+/+ and -/- mice had a two- to threefold increase in urine albumin excretion at 2 and 4 mo of diabetes. At 4 mo, diabetic Gpx1+/+ and -/- mice had equivalent levels of oxidative renal injury (increased kidney reactive oxygen species, kidney lipid peroxidation, urine isoprostanes, kidney deposition of advanced glycoxidation, and nitrosylation end products) and a similar degree of glomerular damage (hypertrophy, hypercellularity, sclerosis), tubular injury (apoptosis and vimentin expression), and renal fibrosis (myofibroblasts, collagen, TGF-beta excretion). A lack of Gpx1 was not compensated for by increased levels of catalase or other Gpx isoforms in diabetic kidneys. Contrary to expectations, this study showed that the high level of Gpx1 expressed in the kidney is not protective against the development of renal oxidative stress and nephropathy in a model of type 1 diabetes.
de Haan
Judy B
JB
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Victoria, Australia.
Stefanovic
Nada
N
Nikolic-Paterson
David
D
Scurr
Lyndee L
LL
Croft
Kevin D
KD
Mori
Trevor A
TA
Hertzog
Paul
P
Kola
Ismail
I
Atkins
Robert C
RC
Tesch
Gregory H
GH
D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D000094765:Glutathione Peroxidase GPX1
C492172:Gpx2 protein, mouse; C116888:Gpx3 protein, mouse; D002374:Catalase; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse