Aldose reductase and the role of the polyol pathway in diabetic nephropathy

被引:232
作者
Dunlop, M [1 ]
机构
[1] Univ Melbourne, Royal Melbourne Hosp, Dept Med, Parkville, Vic 3050, Australia
关键词
aldose reductase; polyol pathway; oxidative stress; carbonyl stress; transgenesis; diabetes mellitus;
D O I
10.1046/j.1523-1755.2000.07702.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. In diabetic renal complications, hyperglycemia may cause damage at a cellular level in both glomerular and tubular locations, often preceding overt dysfunction. Our previous work has implicated aldose reductase in a pathway whereby aldose reductase-induced use of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) drives the pentose phosphate pathway, which culminates in a protein kinase C-induced increase in glomerular prostaglandin production and loss of mesangial cell contractility as a possible cause of hyperfiltration and glomerular dysfunction in diabetes. In this model, aldose reductase inhibition in vitro redresses all aspects of the pathway proposed to lead to hyperfiltration; aldose reductase inhibition in vivo gives only a partial amelioration over the short-term or is without effect in the longer term on microalbuminuria, which follows glomerular and tubular dysfunction. In diabetes, hyperglycemia-induced renal polyol pathway activity does not occur in isolation but instead in tandem with oxidative changes and the production of reactive dicarbonyls and alpha,beta-unsaturated aldehydes. Aldose reductase may detoxify these compounds. We investigated. this aspect in a transgenic rat model with human aldose reductase cDNA under the control of the cytomegalovirus promoter with tubular expression of transgene. Methods. Tubules(S3 region-enriched) from transgenic and control animals were prepared, exposed to oxidative stress, and analyzed to determine the cellular protein dicarbonyl content. Results. In tubules from transgenic animals, oxidative stress-induced dicarbonyls were significantly reduced, an effect not seen when an aldose reductase inhibitor was present. Conclusions. Aldose reductase may both exacerbate and alleviate the production of metabolites that lead to hyperglycemia-induced cellular impairment, with the balance determining the extent of dysfunction.
引用
收藏
页码:S3 / S12
页数:10
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