Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.
BACKGROUND
Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose.


METHODS
PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay.


RESULTS
ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007).


CONCLUSIONS
These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.
Hodgkinson
A D
AD
Department of Molecular Medicine, University of Plymouth, Plymouth, England, United Kingdom.
Søndergaard
K L
KL
Yang
B
B
Cross
D F
DF
Millward
B A
BA
Demaine
A G
AG
D000328:Adult; D000449:Aldehyde Reductase / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000201:enzymology*; D007064:L-Iditol 2-Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D002352:Carrier Proteins; D012333:RNA, Messenger; D007064:L-Iditol 2-Dehydrogenase; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase