Effects of inhibition of the polyol pathway during chronic peritoneal exposure to a dialysis solution.
BACKGROUND
Peritoneal dialysis with glucose- and lactate-containing dialysis solutions stimulates peritoneal angiogenesis and fibrosis. These serious side effects can also be induced by chronic peritoneal exposure to dialysis solutions in nonuremic rats. The high glucose concentrations of the dialysis solutions may saturate physiological glucose metabolism pathways and stimulate the polyol pathway that has been described to damage nerves and vessels in diabetes mellitus. To investigate the role of the polyol pathway in the development of fibrosis and angiogenesis during chronic peritoneal exposure, the rate-limiting aldose reductase activity in the polyol pathway was inhibited in a chronic peritoneal exposure model in the rat, in which different administration routes were compared.


METHODS
Three groups of rats received daily intraperitoneal infusion with lactate/glucose (3.86%)--containing dialysate via a peritoneal catheter with a subcutaneous puncture device, for 14 weeks: group 1 received only the dialysis solution, groups 2 and 3 received, in addition, zopolrestat, administered either orally (group 2) or intraperitoneally (group 3). After sacrifice, omental tissue was examined by histology for the presence of fibrosis (Picro Sirius Red) and the number of blood vessels (CD31).


RESULTS
Histology revealed significantly less Picro Sirius Red-positive tissue in perivascular areas of both experimental groups and submesothelial areas of the oral group in comparison to the control group. There were significantly fewer CD31-positive vessels perfield in both groups treated with zopolrestat compared to the infusion-only group: group 2, 9 (7 - 12); group 3, 17 (13 - 38), compared to group 1, 37 (32 - 39), p < 0.05.


CONCLUSIONS
The combination of peritoneal exposure to dialysis fluids and administration of zopolrestat, a newly developed inhibitor of aldose reductase activity, resulted in less fibrosis and fewer peritoneal vessels than exposure to dialysis fluids only, in a long-term exposure model in the rat. Inhibition of the polyol pathway may thus offer an important contribution to allow long-term continuation of peritoneal dialysis.
van Westrhenen
Roos
R
Division of Nephrology, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. roosvanwestrhenen@hotmail.com
Aten
Jan
J
Aberra
Medhanit
M
Dragt
Cindy A M
CA
Deira
Gregory
G
Krediet
Raymond T
RT
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D052160:Benzothiazoles; D015314:Dialysis Solutions / Q000008:administration & dosage / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D005947:Glucose / Q000008:administration & dosage / Q000009:adverse effects; D007263:Infusions, Parenteral; D019344:Lactic Acid / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010532:Peritoneal Diseases / Q000209:etiology* / Q000517:prevention & control; D010537:Peritoneum / Q000187:drug effects; D010793:Phthalazines / Q000008:administration & dosage*; D011108:Polymers / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013844:Thiazoles / Q000008:administration & dosage*
D052160:Benzothiazoles; D015314:Dialysis Solutions; D004791:Enzyme Inhibitors; D010793:Phthalazines; D011108:Polymers; D013844:Thiazoles; C024617:polyol; C067172:zopolrestat; D019344:Lactic Acid; D000449:Aldehyde Reductase; D005947:Glucose