DIETARY ANTIOXIDANT INHIBITS LIPOPROTEIN OXIDATION AND RENAL INJURY IN EXPERIMENTAL FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Lipid peroxidation may be involved in the pathogenesis of focal segmen tal glomerulosclerosis (FSGS). In the present study we examined whethe r lipid-soluble antioxidants, probucol and vitamin E, could inhibit re nal injury in rats with chronic puromycin aminonucleoside (PA) nephros is and dietary hypercholesterolemia by protecting lipoproteins from ox idation. Male Sprague-Dawley rats received six intraperitoneal injecti ons of PA over a 10 week period and were fed a high cholesterol (HC) d iet (PA-HC) or the same diet supplemented with either 1% probucol or v itamin E (100 IU/kg) for 32 weeks. For comparison, a group of rats rec eived PA injections and a normal diet (PA-normal) with or without prob ucol or vitamin E. Another group rats received saline injections inste ad of PA and were fed a HC diet (Sal-HC) with or without probucol or v itamin E. At the end of the experiment, proteinuria, FSGS and tubuloin terstitial lesions were present in the untreated rats with PA-HC or PA -normal. The magnitude of these lesions was significantly greater in t he PA-HC rats than the PA-normal. In contrast to the PA-HC group with hypercholesterolemia, the PA-normal group did not show hypercholestero lemia from week 16 onwards. The rats with PA-HC alone showed significa ntly higher renal cortical malondialdehyde (MDA) levels and greater su sceptibility of plasma very low density lipoprotein (VLDL) + low densi ty lipoprotein (LDL) to the copper-mediated oxidation than the rats wi th PA-normal or Sal-HC alone. The administration of probucol or vitami n E in the rats with PA-HC significantly reduced the susceptibility of plasma VLDL + LDL to in vitro oxidation, renal cortical MDA level, pr oteinuria, mesangial volume density and magnitude of FSGS and intersti tial lesions. Immunohistochemical staining of renal tissue showed foca l segmental distribution of oxidized LDL (Ox-LDL) in the glomeruli of rats with PA-HC. Administration of probucol or vitamin E reduced the i ntensity of Ox-LDL staining. The staining with ED1 demonstrated that i nfiltrating glomerular macrophages were significantly more prevalent i n the untreated rats with PA-HC than PA-normal or Sal-HC. Treatment wi th probucol or vitamin E significantly reduced the number of glomerula r macrophages in the rats with PA-HC. These results suggest that alime ntary hypercholesterolemia aggravates the renal damage in association with increased renal lipid peroxides in chronic PA nephrosis, and that dietary probucol or vitamin E attenuates renal injury in rats with PA -HC possibly by making lipoproteins resistant to oxidation and by inhi biting intraglomerular macrophage infiltration.