Oxidative stress may contribute to the pathogenesis of diabetic nephropathy (DN),
although the precise regulatory mechanism is still unclear. Recent reports have shown
that chemical molecular chaperone 4-phenylbutyric acid (4-PBA) can suppress oxidative
stress by attenuating endoplasmic reticulum (ER) stress. We therefore hypothesized
that 4-PBA could provide renoprotection through the suppression of oxidative stress
in DN rats. Male Sprague-Dawley (SD) rats were randomly divided into three groups:
a normal control (NC) group, a streptozotocin (STZ)-induced DN model group, and a
DN plus 4-PBA (1g/kg) treatment group. At the end of 4, 8, and 12 weeks, hydroxyproline
content, NADPH oxidase activity and the expression of phosphorylation of inositol-requiring
enzyme-1alpha (p-IRE1alpha), p47phox, nitrotyrosine (NT) and NF-E2-related factor
2 (Nrf2) in the kidneys of all rats were determined; malondialdehyde (MDA) levels
and superoxide dismutase (SOD) activity in serum and urine were also detected; renal
nuclear factor kappaB (NF-kappaB) activity in all of the rats was examined at the
end of 12 weeks. Compared with the NC group, the DN rats showed a significant increase
in hydroxyproline content, NADPH oxidase activity, NF-kappaB activity, the expression
of p-IRE1alpha, p47phox, NT and Nrf2 in renal tissue; markedly, MDA levels were higher
and SOD activity was lower in serum and urine of DN rats than in NC rats for the indicated
time. These alterations were inhibited by the administration of 4-PBA. These findings
first demonstrated that treatment with 4-PBA significantly inhibits the process and
development of diabetic nephropathy in rats through the regulation of ER stress-oxidative
activation.
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