Effects of 4-phenylbutyric acid on the process and development of diabetic nephropathy induced in rats by streptozotocin: Regulation of endoplasmic reticulum stress-oxidative activation

Journal Article · Thu Jul 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

OSTI ID:21460186

Zhifeng, Luo ^[1]; Jiao, Mu; Wei, Qi; Wei, Zeng; Yanhong, Guo; Qi, Pang; Zilin, Ye; Li, Liu; Fahuan, Yuan ^[1]

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1. Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China)

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 (1 g/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-1{alpha} (p-IRE1{alpha}), 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 {kappa}B (NF-{kappa}B) 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-{kappa}B activity, the expression of p-IRE1{alpha}, 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.

• OSTI ID: 21460186
• Journal Information: Toxicology and Applied Pharmacology, Vol. 246, Issue 1-2; Other Information: DOI: 10.1016/j.taap.2010.04.005; PII: S0041-008X(10)00132-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BUTYRIC ACID
ENDOPLASMIC RETICULUM
HYDROXYPROLINE
KIDNEYS
OXIDASES
OXIDATION
RATS
STREPTOZOCIN
STRESSES
SUPEROXIDE DISMUTASE
URINE
AMINES
AMINO ACIDS
ANIMALS
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
ANTINEOPLASTIC DRUGS
AZOLES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CHEMICAL REACTIONS
DRUGS
ENZYMES
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROXY ACIDS
MAMMALS
MATERIALS
MONOCARBOXYLIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
PROTEINS
PYRROLES
PYRROLIDINES
RODENTS
VERTEBRATES
WASTES