Adverse renal effects of the AGE inhibitor pyridoxamine in combination with ACEi in non-diabetic adriamycin-induced renal damage in rats.
OBJECTIVE
Advanced glycation end products (AGEs) are involved in diabetic nephropathy. The AGE inhibitor pyridoxamine (PM) is renoprotective in experimental chronic allograft nephropathy supporting its potential in non-diabetic renal damage.


METHODS
We studied the effects of PM in adriamycin nephropathy (AN; 1.5 mg/kg i.v.). Six weeks after disease induction, treatment started with vehicle (VEH), lisinopril (ACEi; 75 mg/l drinking water), PM (2 g/l) and PM + lisinopril (PM/ACEi) (n = 12 per group) for 18 weeks. Age-matched healthy rats (n = 6) served as controls (CON).


RESULTS
ACEi reduced proteinuria, blood pressure, and renal damage. PM gradually increased blood pressure and not affected proteinuria. In PM/ACEi the antiproteinuric and blood pressure-lowering effects of ACEi were abrogated during long-term treatment. Remarkably, creatinine, focal glomerulosclerosis and interstitial fibrosis were considerably increased under PM/ACEi. Pronounced hypercholesterolemia, which occurred in both PM-treated groups, was accompanied by marked glomerular lipid deposition.


CONCLUSIONS
PM was not renoprotective in AN. By contrast, renal damage was aggravated when PM was combined with ACEi. Despite the fact that there is no current evidence that these findings apply to the drug as used in human diabetic nephropathy, we emphasize the importance of close monitoring of blood pressure, lipids and possible direct toxic effects in future studies with PM in renal patients, especially when combining PM with ACEi.
Waanders
Femke
F
Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.
van Goor
Harry
H
Navis
Gerjan
G
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure; D004317:Doxorubicin / Q000009:adverse effects*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D007674:Kidney Diseases / Q000139:chemically induced*; D008055:Lipids / Q000097:blood; D017706:Lisinopril / Q000494:pharmacology*; D011507:Proteinuria; D011733:Pyridoxamine / Q000009:adverse effects*; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D008055:Lipids; D011733:Pyridoxamine; D004317:Doxorubicin; D017706:Lisinopril