Aldose reductase and the role of the polyol pathway in diabetic nephropathy.
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.
Dunlop
M
M
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. m.dunlop@medicine.unimelb.edu.au
D000449:Aldehyde Reductase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D004075:Diglycerides / Q000096:biosynthesis; D005609:Free Radicals; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism; D018384:Oxidative Stress; D011108:Polymers / Q000378:metabolism*; D051381:Rats
D004075:Diglycerides; D005609:Free Radicals; D011108:Polymers; C024617:polyol; D000449:Aldehyde Reductase; D005947:Glucose