Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats.
BACKGROUND
Advanced glycation end products (AGEs) are involved in diabetic nephropathy (DN). The AGE formation inhibitor pyridoxamine (PM) is renoprotective in DN and in normoglycaemic obese Zucker rats. In chronic allograft nephropathy (CAN), renal AGE accumulation occurs as well.


METHODS
To investigate whether inhibition of AGE formation is renoprotective in CAN, we studied the Fisher 344 to Lewis (F-L) allograft rat model of experimental CAN. Fisher to Fisher (F-F) isografts served as controls. Proteinuria, renal function and renal histology of untreated transplanted rats (F-L n = 8, F-F n = 8) were compared to rats receiving PM 2 g/l in drinking water for 20 weeks starting at transplantation (F-L n = 5, F-F n = 10). All rats received cyclosporin A (1.5 mg/kg/day) for 10 days after transplantation to prevent early acute rejection.


RESULTS
Compared to untreated allografts, PM significantly decreased proteinuria (76 +/- 18 vs 29 +/- 3 mg/day), serum creatinine (130 +/- 12 vs 98 +/- 5 micromol/l), focal glomerulosclerosis (116 +/- 27 vs 16 +/- 5 AU), glomerular macrophage influx (5.6 +/- 0.6 vs 3.3 +/- 1.0), interstitial fibrosis (132 +/- 24 vs 76 +/- 2 AU) and interstitial macrophage influx (47.0 +/- 8.7 vs 15.4 +/- 5.0. Moreover, PM significantly ameliorated tubular accumulation of pentosidine, compared to untreated allografts (2.5 +/- 0.6 vs 0.3 +/- 0.3, all p < 0.05). In the isograft controls, these values did not differ between untreated and PM treated rats.


CONCLUSIONS
PM exerts renoprotective effects and decreases renal pentosidine accumulation in experimental CAN, suggesting a detrimental role for renal AGE accumulation in the pathogenesis of renal damage in this non-diabetic model. These results indicate that inhibition of AGE formation might be a useful adjunct therapy to attenuate CAN.
Waanders
Femke
F
University Medical Centre Groningen, Department of Nephrology, Room 40.4.45, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. F.Waanders@int.umcg.nl
van den Berg
Else
E
Nagai
Ryoji
R
van Veen
Ingrid
I
Navis
Gerjan
G
van Goor
Harry
H
D000818:Animals; D002908:Chronic Disease; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D011733:Pyridoxamine / Q000627:therapeutic use*; D051381:Rats
D017127:Glycation End Products, Advanced; D011733:Pyridoxamine