Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney

Abstract

A significant reduction of renal mass results in proteinuria, glomerulosclerosis, and tubulointerstitial injury, culminating in end-stage chronic renal failure (CRF). The accumulation of lipids in the kidney can cause renal disease. Uptake of oxidized lipoproteins via scavenger receptors, reabsorption of filtered protein-bound lipids via the megalin-cubilin complex, and increased glucose load per nephron can promote lipid accumulation in glomerular, tubular, and interstitial cells in CRF. Cellular lipid homeostasis is regulated by lipid influx, synthesis, catabolism, and efflux. We examined lipid-regulatory factors in the remnant kidney of rats 11 wk after nephrectomy (CRF) or sham operation. CRF resulted in azotemia, proteinuria, lipid accumulation in the kidney, upregulation of megalin, cubilin, mediators of lipid influx (scavenger receptor class A and lectin-like oxidized receptor-1), lipid efflux (liver X receptor α/β and ATP-binding cassette transporter), and fatty acid biosynthesis (carbohydrate-response element binding protein, fatty acid synthase, and acetyl-CoA carboxylase). However, factors involved in cholesterol biosynthesis (sterol regulatory element binding protein, 3-hydroxy-3-methylglutaryl coenzyme A reductase, SCAP, Insig-1, and Insig-2) and fatty acid oxidation (peroxisome proliferator-activated receptor, acyl-CoA oxidase, and liver-type fatty acid binding protein) were reduced in the remnant kidney. Thus CRF results in heavy lipid accumulation in the remnant kidney, which is mediated by upregulation of pathways involved in tubular reabsorption of filtered protein-bound lipids, influx of oxidized lipoproteins and synthesis of fatty acids, and downregulation of pathways involved in fatty acid catabolism.

HDL abnormalities in nephrotic syndrome and chronic kidney disease

“…The ability of HDL to remove cholesterol from lipid-laden macrophages via ABCA-1 is markedly reduced in patients undergoing haemodialysis compared to that of healthy controls 83 . A series of studies have demonstrated an accumulation of neutral lipids in the artery wall and kidneys of rat models of CKD, despite upregulation of ABCA-1 and ABCG1 84,85 . These findings excluded ABCA-1 or ABCG1 deficiency as a potential cause of impaired HDL maturation and reverse cholesterol transport in advanced CKD.…”

Role of dyslipidemia in impairment of energy metabolism, oxidative stress, inflammation and cardiovascular disease in chronic kidney disease

“…HDL cholesterol is reduced, maturation of CEpoor to CE-rich HDL-2 is impaired [8] and antioxidant, anti-inflammatory and reverse cholesterol transport activities of HDL are impaired in most ESRD patients [22,23]. These abnormalities are due to (a) reduced production and oxidative modification of ApoAI [8,24,25] which lead to HDL deficiency and impaired HDL binding to the gateway of cholesterol efflux (ATP binding cassette A1), (b) upregulation of acyl-CoA cholesterol acyltransferase (ACAT) [26][27][28][29] which limits release of intracellular cholesterol, (c) lecithin cholesterol acyltransferase (LCAT) deficiency [30] which impairs HDL maturation, and (d) paraoxonase and glutathione peroxidase deficiencies [28] which limit the ability of HDL to reduce oxidized LDL.…”

Lipotoxicity in Diabetic Nephropathy

“…In a recent study by Kim and colleagues, experimental 5/6 nephrectomy lead to upregulation of ACC with marked lipid accumulation in the remnant kidney along with other important changes in the molecular architecture of cellular lipid homeostasis, including intense upregulation of the proximal tubule megalin-cubulin complex, which facilitates uptake of protein-bound lipids; marked upregulation of scavenger receptor class A and class E lectin-like oxidized LDL receptor 1, which mediate uptake of oxidized lipids and lipoproteins; downregulation of hydroxy-methylglutaryl CoA reductase; downregulation of SREBP-1 and PPAR␣; and upregulation of ChREBP (48). Megalin has been identified as a key molecule in the pathogenesis of tubulointerstitial injury, providing a molecular link between PTC lipid overload and renal failure (49).…”