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.