Treatment of Hyperlipidemia with Probucol Suppresses the Development of Focal and Segmental Glomerulosclerosis in Chronic Aminonucleoside Nephrosis

Abstract

We have recently reported that a lipid-lowering agent, probucol, reduces proteinuria in puromycin aminonucleoside (PA)-induced nephrotic rats (PAN). In this study, we examined whether a long-term treatment of hyperlipidemia with probucol can suppress the development of focal and segmental glomerulosclerosis (FSGS) in chronic PAN. A chronic PAN model was made with repeated intraperitoneal injections of PA (initially 100 mg/kg body weight followed by 25 mg/kg 5 times at 2-week intervals). Two weeks after the first injection of PA, either normal rat chow with or without 1% probucol was given to the nephrotic rats for 10 weeks. Chronic PAN exhibited remarkable proteinuria, hypoalbuminemia and severe hyperlipidemia with all lipoprotein fractions increased. Probucol treatment significantly reduced the lipid concentration in all major lipoproteins, significantly reduced proteinuria and increased plasma albumin concentration. Plasma albumin inversely correlated with cholesterol or phospholipid in low-density and high-density lipoproteins, suggesting that the lipid-lowering effect of probucol may ameliorate the hypoalbuminemia associated with nephrosis. In light microscopic examination, various degrees of FSGS with tubuloin-terstitial lesions were observed in the renal cortex from chronic PAN. The degree of FSGS was scored from grades 1 to 4 according to severity. One half of the untreated PAN (⁴/₈) was classified into grade 4 and the other into grades 2 or 3, whilst one half of treated PAN (⁴/₈) was classified either into grade 1 or 2. The grading of FSGS correlated negatively with plasma albumin concentration. These results demonstrate that probucol is highly effective upon nephrotic hyperlipidemia and suggest that a long-term treatment of secondary hyperlipidemia can suppress progressive renal injury associated with chronic nephrosis.

Effects of Probucol on Renal Function and Urinary Protein Excretion in Spontaneously Hypercholesterolemic Rats Fed a Normal or High Cholesterol Diet

“…They concluded that probucol rendered LDL cholesterol resistant to oxidative modification as shown in a previous study [36]. Similarly, progressive renal injury by chronic puromycin aminonucleoside nephrosis was inhibited by probucol treatment [9,40]. On the other hand, the drug failed to prevent increasing fibrosis in the acute model by puromycin aminonucleoside [41], while the combination of probucol and vitamin E treatment attenuated interstitial inflammation [42].…”

“…Treatment by antilipemic agents has been shown to ameliorate renal injury in hyperlipidemic animals. The effects seem to be brought about partly by the lipid-lowering action of the drugs used in each study, because the serum Nakao/Nosaka/Imaki/Noiri/Toda/Doi/ Suzuki/Fujita/Kimura cholesterol levels of experimental animals are reduced to some extent by the treatment [6,7,9,34,35]. However, probucol, a lipid-lowering agent, has also been reported to have an antioxidant effect, which was clearly shown in the experiment by Kita et al [36] using the Watanabe hereditable hyperlipidemic rabbit model to ameliorate atherosclerosis.…”

“…A lipid-induced renal injury model of rats was produced in 6 weeks. [1,3,4], and animal models of endogenous hyperlipidemia have been found to develop glomerular sclerosis [5][6][7], while mitigation of the glomerular injury by the pharmacological treatment of the hyperlipidemia has been shown [6][7][8][9]. Spontaneously hypercholesterolemic (SHC) rats were originally bred from the Sprague-Dawley strain, and males develop hypercholesterolemia, massive proteinuria, and glomerular sclerosis with age [10,11].…”

Glomerulosclerosis: The Final Pathway Is Clarified, but Can We Deal with the Triggers?

“…No doubt, the same agent could be used to explore the situation in glomerulonephritides. Probucol is an effective antioxidant that is used in man [57], and we know that it can stop develop ment of focal glomerulosclerosis [58],…”

“…Probucol is an anti-oxidant that also lowers the blood lipids. Probucol suppresses focal glomerulosclerosis [58,98] …”