Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis

Abstract

Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.

Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibition Ameliorates Proteinuria, Hyperlipidemia, Lecithin-Cholesterol Acyltransferase, SRB-1, and Low-Denisty Lipoprotein Receptor Deficiencies in Nephrotic Syndrome

“…41 Upregulation of hepatic ACAT-2 in the untreated nephrotic group was accompanied by a nearly 6-fold rise in cholesterol content of apoB-containing lipoproteins (LDL plus VLDL) in the fasting plasma. Given the critical role of ACAT in production of VLDL and hence its final byproduct, LDL, upregulation of hepatic ACAT-2 can contribute to this abnormality by compounding the effects of LDL receptor 7,8 and VLDL receptor 22,23,25 deficiencies in NS. Administration of IC-976, an inhibitor of ACAT-1 and -2, normalized microsomal ACAT activity, which led to a rise in microsomal free cholesterol (diminished ACAT-mediated esterification) and a decline in plasma total, LDL, and VLDL cholesterol levels.…”

“…5,6 Nephrotic dyslipidemia is marked by hypercholesterolemia; hypertriglyceridemia; elevated plasma concentration and impaired clearance of LDL, VLDL, and IDL; impaired maturation and diminished clearance of HDL; and increased plasma lipoprotein (a). [1][2][3][4] These abnormalities are largely a result of dysregulation of the key enzymes and receptors involved in lipid metabolism: (1) LDL receptor deficiency, 7,8 which, in part, accounts for elevated plasma level and impaired clearance of LDL 3,9,10 ; (2) lecithin-cholesterol acyltransferase (LCAT) deficiency, 11 elevated plasma cholesterol ester transfer protein (CETP), 12 and diminished hepatic SRB-1 (HDL receptor), 13 which collectively accounts for abnormal composition, impaired maturation, and defective clearance of HDL 3,14 -16 ; (3) dysregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7␣-hydroxylase (rate-limiting enzyme in cholesterol conversion to bile acid), leading to development and maintenance of hypercholesterolemia 8,17,18 ; (4) upregulations of hepatic biosynthesis and diminished catabolism of apolipoprotein (apo) B-100 and increased production of lipoprotein (a), which contribute to their elevated plasma levels in NS 19,20 ; and (5) downregulations of lipoprotein lipase (LPL) VLDL receptor [21][22][23] and hepatic lipase 24,25 coupled with upregulations of hepatic acylcoenzyme A:diacylglycerol acyltransferase (DGAT, the final step in triglyceride biosynthesis), 26 acetyl-coenzyme A carboxylase, and fatty acid synthase (key enzymes in fatty acid production). 27 These abnormalities account for increased hepatic synthesis, 28 -30 impaired clearance, and elevated plasma triglycerides, VLDL, and IDL in NS (reviewed in Reference 1).…”

HDL abnormalities in nephrotic syndrome and chronic kidney disease

“…In vitro analyses have demonstrated a marked reduction in heparin-releasable lipase activity in the livers of nephrotic rats compared to control rats 45 . Moreover, marked downregulation of hepatic lipase expression and activity in hypercholesterolaemic Imai rats with spontaneous focal segmental glomerulo sclero sis, and rats with puromycin aminoglycoside-induced nephrotic syndrome has also been reported 46,47 . Acquired hepatic lipase deficiency, therefore, contributes to triglycer ide enrichment of HDL in nephrotic syndrome.…”

Oral adsorbent AST-120 ameliorates endothelial dysfunction independent of renal function in rats with subtotal nephrectomy

“…8 Furthermore, experimental studies also showed that AST-120 prevents the progression of renal injury in rats with subtotal nephrectomy and focal glomerulosclerosis. 9,10 The renoprotective effects of AST-120 are thought to be mediated by reduced interstitial fibrosis (IF) through downregulation of transforming growth factor-b1 and tissue inhibitor of metalloproteinase-1 in uremic and diabetic rat kidneys. 11,12 There is some evidence that AST-120 can also retard the development of CVD in patients with CKD.…”