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1 Centre for Functional Genomics and Human Disease, Monash University, Monash Institute of Reproduction and Development, Clayton, Victoria, Australia
2 Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
3 Department of Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia
4 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
5 Merck Research Laboratories, Rahway, New Jersey, USA
* To whom correspondence should be addressed. E-mail: gtesch{at}hotmail.com.
In many diseases, including progressive renal disorders, tissue injury and pathological
intracellular signalling events are dependent on oxidative stress. Glutathione peroxidase-1
(Gpx1) is an antioxidant enzyme which 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 (100mg/kg) on two consecutive days. Diabetic
Gpx1 +/+ and -/- mice with equivalent blood glucose levels (23 ± 4 mM) were selected and
examined after 4 months of diabetes. Compared to normal mice, diabetic Gpx1 +/+ and -/-
mice had a 2-3 fold increase in urine albumin excretion at 2 and 4 months of diabetes. At 4
months, 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-
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 has shown 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.
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