Abstract
To evaluate RNA oxidation in the early stage of diabetic nephropathy, we applied an accurate method based on isotope dilution high-performance liquid chromatography-triple quadruple mass spectrometry to analyze the oxidatively generated guanine nucleosides in renal tissue and urine from db/db mice of different ages. We further investigated the relationship between these oxidative stress markers, microalbumin excretion, and histological changes. We found that the levels of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were increased in the urine and renal tissue of db/db mice and db/db mice with early symptoms of diabetic nephropathy suffered from more extensive oxidative damage than lean littermate control db/m mice. Importantly, in contrast to the findings in db/m mice, the 8-oxoGuo levels in the urine and renal tissue of db/db mice were higher than those of 8-oxodGuo at four weeks. These results indicate that RNA oxidation is more apparent than DNA oxidation in the early stage of diabetic nephropathy. RNA oxidation may provide new insight into the pathogenesis of diabetic nephropathy, and urinary 8-oxoGuo may represent a novel, noninvasive, and easily detected biomarker of diabetic kidney diseases if further study could clarify its source and confirm these results in a large population study.
Highlights
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the strongest predictor of mortality in patients with diabetes [1, 2]
Since DKD is the strongest predictor of mortality in patients with diabetes [1, 2], it is important to determine whether or not there is a relationship between RNA oxidation and diabetic nephropathy
Various methods have been used to determine the levels of 8-oxodGuo, and historically, the quantitation of urinary 8oxodGuo in diabetic nephropathy research has mainly been based on HPLC with electrochemical detection (HPLCECD) or enzyme-linked immunosorbent assay (ELISA) [5, 6, 20,21,22], methods that are hampered by insufficient specificity and sensitivity [23]
Summary
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the strongest predictor of mortality in patients with diabetes [1, 2]. Previous reports have indicated that DNA marker 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) oxidation is a useful clinical marker of diabetic nephropathy (DN) [4,5,6,7], but the conclusion is somewhat controversial [8]. RNA oxidation is considered to be a marker of an early stage at which the clinical symptoms are very discrete in some diseases [9, 10] and may be useful for the prevention and therapy of these diseases. The RNA oxidation marker 8-oxo-7,8-dihydroguanosin (8-oxoGuo) was recently identified as an independent predictor of mortality in patients with established and treated type 2 diabetes [11]. Since DKD is the strongest predictor of mortality in patients with diabetes [1, 2], it is important to determine whether or not there is a relationship between RNA oxidation and diabetic nephropathy
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