Dietary antioxidant inhibits lipoprotein oxidation and renal injury in experimental focal segmental glomerulosclerosis

Abstract

Lipid peroxidation may be involved in the pathogenesis of focal segmental glomerulosclerosis (FSGS). In the present study we examined whether lipid-soluble antioxidants, probucol and vitamin E, could inhibit renal injury in rats with chronic puromycin aminonucleoside (PA) nephrosis and dietary hypercholesterolemia by protecting lipoproteins from oxidation. Male Sprague-Dawley rats received six intraperitoneal injections of PA over a 10 week period and were fed a high cholesterol (HC) diet (PA-HC) or the same diet supplemented with either 1% probucol or vitamin E (100 IU/kg) for 32 weeks. For comparison, a group of rats received PA injections and a normal diet (PA-normal) with or without probucol or vitamin E. Another group rats received saline injections instead of PA and were fed a HC diet (Sal-HC) with or without probucol or vitamin E. At the end of the experiment, proteinuria, FSGS and tubulointerstitial lesions were present in the untreated rats with PA-HC or PA-normal. The magnitude of these lesions was significantly greater in the PA-HC rats than the PA-normal. In contrast to the PA-HC group with hypercholesterolemia, the PA-normal group did not show hypercholesterolemia from week 16 onwards. The rats with PA-HC alone showed significantly higher renal cortical malondialdehyde (MDA) levels and greater susceptibility of plasma very low density lipoprotein (VLDL) + low density lipoprotein (LDL) to the copper-mediated oxidation than the rats with PA-normal or Sal-HC alone. The administration of probucol or vitamin E in the rats with PA-HC significantly reduced the susceptibility of plasma VLDL + LDL to in vitro oxidation, renal cortical MDA level, proteinuria, mesangial volume density and magnitude of FSGS and interstitial lesions. Immunohistochemical staining of renal tissue showed focal segmental distribution of oxidized LDL (Ox-LDL) in the glomeruli of rats with PA-HC. Administration of probucol or vitamin E reduced the intensity of Ox-LDL staining. The staining with ED1 demonstrated that infiltrating glomerular macrophages were significantly more prevalent in the untreated rats with PA-HC than PA-normal or Sal-HC. Treatment with probucol or vitamin E significantly reduced the number of glomerular macrophages in the rats with PA-HC. These results suggest that alimentary 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 inhibiting intraglomerular macrophage infiltration.

High cholesterol diet leads to oxidant load and peroxidation in the rabbit kidney tissue

“…Several lines of evidence indicate that oxidant stress is a pathogenic factor in lipid-induced nephropathy. By immunohistology, oxidatively modifi ed lipoproteins were demonstrated in focal segmental glomerulosclerosis in rat and humans (57)(58)(59). However, the steps leading to oxidative modifi cation of proteins and lipoproteins have not been elucidated in detail yet.…”

Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs

“…In the kidney, vitamin E attenuates chronic injury associated with glomerulosclerosis (18) or aging (19), and prevents renal interstitial fibrosis associated with HC (20). We have previously shown that combined administration of vitamins E and C in experimental HC reduced LDL oxidizability and preserved renal endothelial function (9).…”

Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs

“…Similarly, we have shown that this condition can induce functional vascular changes in the kidney, both in vivo and in vitro (50), which precede the onset of overt atherosclerotic lesions (10,20,42). Subsequently, HC subjects may develop glomerulosclerosis (24), ox-LDL deposition (35,36), and chronic tubulointerstitial damage (25). Increased oxidative stress appears to be one of the main pathogenic mechanisms mediating lipid-induced nephropathy, and involves increased generation of ROS, decreased NO bioavailability, and consequently endothelial dysfunction, a condition characterized by a blunted endotheliumdependent vasodilator response.…”

“…Moreover, HC has been demonstrated to be an independent risk factor for the onset (10) and progression (22) of renal disease and can both induce and worsen renal glomerular, interstitial, and vascular damage (30,35). We have previously shown (11,20,42) that even a short exposure to diet-induced HC is associated with increased formation of oxidized LDL (ox-LDL) and reactive oxygen species (ROS).…”