Metabolism, energetics, and lipid biology in the podocyte - Cellular cholesterol mediated glomerular injury

Frontiers in Endocrinology

Volumn 5, Issue SEP, 2014, Pages

  Merscher, Sandra ^a   Pedigo, Christopher E ^a   Mendez, Armando J ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

ABCA1; Apolipoprotein; Cholesterol; Glomerular disease; Kidney disease; Nephropathy; Podocyte; Renal disease; Reverse cholesterol transport

Indexed keywords

ABC TRANSPORTER A1; ABC TRANSPORTER G1; ADVANCED GLYCATION END PRODUCT; ALISKIREN; ALPHA ACTININ 4; APOLIPOPROTEIN A1; APOLIPOPROTEIN B; APOLIPOPROTEIN E; APOLIPOPROTEIN L1; APOLIPOPROTEIN M; CARNITINE PALMITOYLTRANSFERASE I; CHOLESTEROL ACYLTRANSFERASE; COMPLEMENT COMPONENT C3; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; LIPOPROTEIN X; LIVER X RECEPTOR ALPHA; LIVER X RECEPTOR BETA; LOW DENSITY LIPOPROTEIN CHOLESTEROL; NEPHRIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PHOSPHATIDYLCHOLINE STEROL ACYLTRANSFERASE; PODOCIN; SCAVENGER RECEPTOR BI; STEROL REGULATORY ELEMENT BINDING PROTEIN; STREPTOZOCIN; TRANSIENT RECEPTOR POTENTIAL CHANNEL 6; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALSARTAN; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL;

ACUTE KIDNEY FAILURE; ARTICLE; BIOACCUMULATION; CELL ENERGY; CELL METABOLISM; CHOLESTEROL ESTERIFICATION; CHOLESTEROL SYNTHESIS; CHOLESTEROL TRANSPORT; CHRONIC KIDNEY DISEASE; DIABETIC NEPHROPATHY; ENDOPLASMIC RETICULUM MEMBRANE; ENERGY TRANSFER; FOCAL GLOMERULOSCLEROSIS; GENE MUTATION; GENETIC POLYMORPHISM; GLOMERULOPATHY; GLOMERULUS BASEMENT MEMBRANE; HUMAN; HYPERLIPOPROTEINEMIA TYPE 3; INFLAMMATION; INTRACELLULAR SIGNALING; LIPID HOMEOSTASIS; NIEMANN PICK DISEASE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PODOCYTE; PROTEIN EXPRESSION; PROTEINURIA; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; TANGIER DISEASE;

EID: 84907681499     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2014.00169     Document Type: Article

References (167)

1. Somlo, S. & Mundel, P. Getting a foothold in nephrotic syndrome. Nat Genet 24, 333-335 (2000).
2. Ruotsalainen, V., et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 96, 7962-7967 (1999).
3. Tryggvason, K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 10, 2440-2445 (1999).
4. Kestila, M., et al. Positionally cloned gene for a novel glomerular protein-- nephrin--is mutated in congenital nephrotic syndrome. Mol Cell 1, 575-582 (1998).
5. Boute, N., et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24, 349-354 (2000).
6. Li, C., Ruotsalainen, V., Tryggvason, K., Shaw, A.S. & Miner, J.H. CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. American journal of physiology. Renal physiology 279, F785-792 (2000).
7. Winn, M.P., et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308, 1801-1804 (2005).
8. Kaplan, J.M., et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24, 251-256 (2000).
9. Huber, T.B., et al. Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci U S A 103, 17079- 17086 (2006).
10. Schermer, B. & Benzing, T. Lipid-protein interactions along the slit diaphragm of podocytes. J Am Soc Nephrol 20, 473-478 (2009).
11. Tabas, I. Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. The Journal of clinical investigation 110, 905-911 (2002).
12. Hua, X., et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci U S A 90, 11603-11607 (1993).
13. Yokoyama, C., et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75, 187-197 (1993).
14. Brown, M.S. & Goldstein, J.L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proceedings of the National Academy of Sciences 96, 11041-11048 (1999).
15. McPherson, R. & Gauthier, A. Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis. Biochemistry and Cell Biology 82, 201-211 (2004).
16. Ye, J. & DeBose-Boyd, R.A. Regulation of Cholesterol and Fatty Acid Synthesis. Cold Spring Harbor Perspectives in Biology 3(2011).
17. Goldstein, J.L. & Brown, M.S. The LDL receptor. Arterioscler Thromb Vasc Biol 29, 431-438 (2009).
18. Abi-Mosleh, L., Infante, R.E., Radhakrishnan, A., Goldstein, J.L. & Brown, M.S. Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells. Proc Natl Acad Sci U S A 106, 19316-19321 (2009).
19. Maxfield, F.R. & Wustner, D. Intracellular cholesterol transport. The Journal of clinical investigation 110, 891-898 (2002).
20. Goldstein, J.L. & Brown, M.S. The LDL Receptor. Arteriosclerosis, Thrombosis, and Vascular Biology 29, 431-438 (2009).
21. Kellner-Weibel, G., Geng, Y.J. & Rothblat, G.H. Cytotoxic cholesterol is generated by the hydrolysis of cytoplasmic cholesteryl ester and transported to the plasma membrane. Atherosclerosis 146, 309-319 (1999).
22. Warner, G.J., Stoudt, G., Bamberger, M., Johnson, W.J. & Rothblat, G.H. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. The Journal of biological chemistry 270, 5772-5778 (1995).
23. Yao, P.M. & Tabas, I. Free cholesterol loading of macrophages is associated with widespread mitochondrial dysfunction and activation of the mitochondrial apoptosis pathway. The Journal of biological chemistry 276, 42468-42476 (2001).
24. Ghosh, S. Macrophage cholesterol homeostasis and metabolic diseases: critical role of cholesteryl ester mobilization. Expert review of cardiovascular therapy 9, 329-340 (2011).
25. Rosenson, R.S., et al. Cholesterol Efflux and Atheroprotection: Advancing the Concept of Reverse Cholesterol Transport. Circulation 125, 1905-1919 (2012).
26. Keane, W.F., Tomassini, J.E. & Neff, D.R. Lipid abnormalities in patients with chronic kidney disease. Contributions to nephrology 171, 135-142 (2011).
27. Majumdar, A. & Wheeler, D.C. Lipid abnormalities in renal disease. Journal of the Royal Society of Medicine 93, 178-182 (2000).
28. Vaziri, N.D. & Norris, K. Lipid disorders and their relevance to outcomes in chronic kidney disease. Blood Purif 31, 189-196 (2011).
29. Nestel, P.J., Fidge, N.H. & Tan, M.H. Increased lipoprotein-remnant formation in chronic renal failure. The New England journal of medicine 307, 329-333 (1982).
30. Al-Shahrouri, H.Z., et al. NMR identifies atherogenic lipoprotein abnormalities in early diabetic nephropathy that are unrecognized by conventional analysis. Clinical nephrology 73, 180-189 (2010).
31. Kuchta, A., et al. Estimation of oxidative stress markers in chronic kidney disease. Kidney & blood pressure research 34, 12-19 (2011).
32. de Boer, I.H. & Brunzell, J.D. HDL in CKD: how good is the "good cholesterol?". Journal of the American Society of Nephrology: JASN 25, 871-874 (2014).
33. Calabresi, L., et al. Acquired lcat deficiency as a major factor in lowering plasma hdl levels in chronic kidney disease. Journal of internal medicine (2014).
34. Peake, K.B. & Vance, J.E. Defective cholesterol trafficking in Niemann- Pick C-deficient cells. FEBS Lett 584, 2731-2739 (2010).
35. Oikawa, S., et al. Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol 8, 820-823 (1997).
36. Khera, A.V., et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. The New England journal of medicine 364, 127-135 (2011).
37. Le Lay, S., et al. Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. The Journal of biological chemistry 276, 16904-16910 (2001).
38. Avram, M.M., et al. Cholesterol and lipid disturbances in renal disease: the natural history of uremic dyslipidemia and the impact of hemodialysis and continuous ambulatory peritoneal dialysis. Am J Med 87, 55N-60N (1989).
39. Joven, J., et al. Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome. The New England journal of medicine 323, 579- 584 (1990).
40. Wheeler, D.C. Lipid abnormalities in the nephrotic syndrome: the therapeutic role of statins. J Nephrol 14 Suppl 4, S70-75 (2001).
41. Attman, P.O., Samuelsson, O. & Alaupovic, P. Lipoprotein metabolism and renal failure. Am J Kidney Dis 21, 573-592 (1993).
42. Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M. & Gafter, U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 55, 561-572 (2013).
43. Kimmelstiel, P. & Wilson, C. Intercapillary Lesions in the Glomeruli of the Kidney. Am J Pathol 12, 83-98 87 (1936).
44. Moorhead, J.F., Chan, M.K., El-Nahas, M. & Varghese, Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 2, 1309-1311 (1982).
45. Keane, W.F., O'Donnell, M.P., Kasiske, B.L. & Schmitz, P.G. Lipids and the progression of renal disease. J Am Soc Nephrol 1, S69-74 (1990).
46. Blue, M.L., Protter, A.A. & Williams, D.L. Biosynthesis of apolipoprotein B in rooster kidney, intestine, and liver. The Journal of biological chemistry 255, 10048-10051 (1980).
47. Blue, M.L., Ostapchuk, P., Gordon, J.S. & Williams, D.L. Synthesis of apolipoprotein AI by peripheral tissues of the rooster. A possible mechanism of cellular cholesterol efflux. The Journal of biological chemistry, 257, 11151-11159 (1982).
48. Tarugi, P., et al. Secretion of apoB- and apoA-I-containing lipoproteins by chick kidney. J Lipid Res 39, 731-743 (1998).
49. Xu, N. & Dahlback, B. A novel human apolipoprotein (apoM). The Journal of biological chemistry 274, 31286-31290 (1999).
50. Blue, M.L., Williams, D.L., Zucker, S., Khan, S.A. & Blum, C.B. Apolipoprotein E synthesis in human kidney, adrenal gland, and liver. Proc Natl Acad Sci U S A 80, 283-287 (1983).
51. Grone, H.J., et al. Receptor mediated uptake of apo B and apo E rich lipoproteins by human glomerular epithelial cells. Kidney Int 37, 1449- 1459 (1990).
52. Madhavan, S.M., et al. APOL1 localization in normal kidney and nondiabetic kidney disease. J Am Soc Nephrol 22, 2119-2128 (2011).
53. Merscher-Gomez, S., et al. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes (2013).
54. Toyota, K., et al. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet 58, 254-258 (2013).
55. Matsunaga, A., et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int 56, 421-427 (1999).
56. Saito, T., Ishigaki, Y., Oikawa, S. & Yamamoto, T.T. Etiological significance of apolipoprotein E mutations in lipoprotein glomerulopathy. Trends Cardiovasc Med 12, 67-70 (2002).
57. Zhang, P., Matalon, R., Kaplan, L., Kumar, A. & Gallo, G. Lipoprotein glomerulopathy: first report in a Chinese male. Am J Kidney Dis 24, 942- 950 (1994).
58. Amatruda, J.M., Margolis, S. & Hutchins, G.M. Type 3 hyperlipoproteinemia with mesangial foam cells in renal glomeruli. Arch Pathol 98, 51-54 (1974).
59. Sakatsume, M., et al. Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity. Kidney Int 59, 1911-1918 (2001).
60. Ruiz, J., et al. The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res 46, 1721-1731 (2005).
61. Horita, K., Eto, M. & Makino, I. Apolipoprotein E2, renal failure and lipid abnormalities in non-insulin-dependent diabetes mellitus. Atherosclerosis 107, 203-211 (1994).
62. Yorioka, N., Nishida, Y., Oda, H., Watanabe, T. & Yamakido, M. Apolipoprotein E polymorphism in IgA nephropathy. Nephron 83, 246-249 (1999).
63. Kimura, H., et al. Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM. Am J Kidney Dis 31, 666-673 (1998).
64. Piedrahita, J.A., Zhang, S.H., Hagaman, J.R., Oliver, P.M. & Maeda, N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A 89, 4471-4475 (1992).
65. Feussner, G., Dobmeyer, J., Grone, H.J., Lohmer, S. & Wohlfeil, S. A 10- bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet 58, 281-291 (1996).
66. Ishigaki, Y., et al. Virus-mediated transduction of apolipoprotein E (ApoE)- sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. The Journal of biological chemistry 275, 31269-31273 (2000).
67. Wen, M., et al. Renal injury in apolipoprotein E-deficient mice. Lab Invest 82, 999-1006 (2002).
68. Ishimura, A., et al. Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice. Clin Exp Nephrol 13, 430-437 (2009).
69. Mazzolai, L., et al. Severe hyperlipidemia causes impaired reninangiotensin system function in apolipoprotein E deficient mice. Atherosclerosis 186, 86-91 (2006).
70. Bruneval, P., et al. Mesangial expansion associated with glomerular endothelial cell activation and macrophage recruitment is developing in hyperlipidaemic apoE null mice. Nephrol Dial Transplant 17, 2099-2107 (2002).
71. Lassila, M., et al. Accelerated nephropathy in diabetic apolipoprotein eknockout mouse: role of advanced glycation end products. J Am Soc Nephrol 15, 2125-2138 (2004).
72. Bagavant, H., et al. Deficiency of a transcriptional regulator, inhibitor of differentiation 3, induces glomerulonephritis in apolipoprotein E-deficient mice: a model linking hyperlipidemia and renal disease. Am J Pathol 179, 651-660 (2011).
73. Feng, X., et al. ApoE-/-Fas-/- C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia. J Lipid Res, 48, 794-805 (2007).
74. Arora, S., et al. Human immunodeficiency virus downregulates podocyte apoE expression. American journal of physiology. Renal physiology 297, F653-661 (2009).
75. van Goor, H., et al. Renal apolipoproteins in nephrotic rats. Am J Pathol 142, 1804-1812 (1993).
76. Bruschi, M., et al. Apolipoprotein E in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Kidney Int 63, 686-695 (2003).
77. Faber, K., Hvidberg, V., Moestrup, S.K., Dahlback, B. & Nielsen, L.B. Megalin is a receptor for apolipoprotein M, and kidney-specific megalindeficiency confers urinary excretion of apolipoprotein M. Mol Endocrinol 20, 212-218 (2006).
78. Leheste, J.R., et al. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol 155, 1361-1370 (1999).
79. Prabakaran, T., et al. Receptor-mediated endocytosis of alphagalactosidase A in human podocytes in Fabry disease. PLoS One 6, e25065 (2011).
80. Kerjaschki, D., et al. Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis. The Journal of clinical investigation 100, 2303-2309 (1997).
81. Kopp, J.B., et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 22, 2129-2137 (2011).
82. Tzur, S., et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet, 128, 345-350 (2010).
83. Genovese, G., et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841-845 (2010).
84. Norum, K.R. & Gjone, E. Familial serum-cholesterol esterification failure. A new inborn error of metabolism. Biochim Biophys Acta 144, 698-700 (1967).
85. Glomset, J.A., Nichols, A.V., Norum, K.R., King, W. & Forte, T. Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency. Further studies of very low and low density lipoprotein abnormalities. The Journal of clinical investigation 52, 1078-1092 (1973).
86. Ohta, Y., et al. Nephropathy of familial lecithin-cholesterol acyltransferase deficiency: report of a case. Am J Kidney Dis 7, 41-46 (1986).
87. Borysiewicz, L.K., Soutar, A.K., Evans, D.J., Thompson, G.R. & Rees, A.J. Renal failure in familial lecithin: cholesterol acyltransferase deficiency. Q J Med, 51, 411-426 (1982).
88. Seidel, D., Agostini, B. & Muller, P. Sturucture of an abnormal plasma lipoprotein (LP-X) characterizing obstructive jaundice. Biochim Biophys Acta 260, 146-152 (1972).
89. Torsvik, H., et al. Identification of the abnormal cholestatic lipoprotein (LPX) in familial lecithin:Cholesterol acyltransferase deficiency. FEBS Lett 24, 165-168 (1972).
90. McLean, J., Wion, K., Drayna, D., Fielding, C. & Lawn, R. Human lecithincholesterol acyltransferase gene: complete gene sequence and sites of expression. Nucleic Acids Res, 14, 9397-9406 (1986).
91. Hixson, J.E., Driscoll, D.M., Birnbaum, S. & Britten, M.L. Baboon lecithin cholesterol acyltransferase (LCAT): cDNA sequences of two alleles, evolution, and gene expression. Gene, 128, 295-299 (1993).
92. Liu, Y.H., et al. Characteristic, polymorphism and expression distribution of LCAT gene in a Mongolian gerbil model for hyperlipidemia. Exp Mol Pathol (2014).
93. Sakai, N., et al. Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency. The Journal of biological chemistry, 272, 7506- 7510 (1997).
94. Ng, D.S., et al. Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I. The Journal of biological chemistry 272, 15777-15781 (1997).
95. Lambert, G., et al. Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice. The Journal of biological chemistry 276, 15090-15098 (2001).
96. Zhu, X., et al. A novel in vivo lecithin-cholesterol acyltransferase (LCAT)- deficient mouse expressing predominantly LpX is associated with spontaneous glomerulopathy. Am J Pathol 165, 1269-1278 (2004).
97. Pentchev, P.G., Blanchette-Mackie, E.J. & Dawidowicz, E.A. The NP-C gene: a key to pathways of intracellular cholesterol transport. Trends Cell Biol 4, 365-369 (1994).
98. Pentchev, P.G., et al. A defect in cholesterol esterification in Niemann- Pick disease (type C) patients. Proc Natl Acad Sci U S A 82, 8247-8251 (1985).
99. Loftus, S.K., et al. Murine Model of Niemann-Pick C Disease: Mutation in a Cholesterol Homeostasis Gene. Science 277, 232-235 (1997).
100. Liao, Y.J., et al. Characterization of Niemann-Pick Type C2 protein expression in multiple cancers using a novel NPC2 monoclonal antibody. PLoS One 8, e77586 (2013).
101. Grafft, C.A., Fervenza, F.C., Semret, M.H., Orloff, S. & Sethi, S. Renal involvement in Neimann-Pick Disease. NDT Plus 2, 448-451 (2009).
102. Philit, J.B., et al. Membranoproliferative glomerulonephritis type II and Niemann-Pick disease type C. Nephrol Dial Transplant 17, 1829-1831 (2002).
103. Liu, B., et al. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse. Proc Natl Acad Sci U S A 106, 2377-2382 (2009).
104. Ramirez, C.M., et al. Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life. Pediatr Res 68, 309-315 (2010).
105. Davidson, C.D., et al. Chronic cyclodextrin treatment of murine Niemann- Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4, e6951 (2009).
106. Mott, S., et al. Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations. Atherosclerosis 152, 457-468 (2000).
107. Bodzioch, M., et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22, 347-351 (1999).
108. Brooks-Wilson, A., et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22, 336-345 (1999).
109. Rust, S., et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22, 352-355 (1999).
110. Ferrans, V.J. & Fredrickson, D.S. The pathology of Tangier disease. A light and electron microscopic study. Am J Pathol 78, 101-158 (1975).
111. Mautner, S.L., et al. The heart in Tangier disease. Severe coronary atherosclerosis with near absence of high-density lipoprotein cholesterol. Am J Clin Pathol 98, 191-198 (1992).
112. Christiansen-Weber, T.A., et al. Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency. Am J Pathol 157, 1017-1029 (2000).
113. Orso, E., et al. Transport of lipids from golgi to plasma membrane is defective in tangier disease patients and Abc1-deficient mice. Nat Genet 24, 192-196 (2000).
114. Proctor, G., et al. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes. Diabetes 55, 2502-2509 (2006).
115. Wang, W., et al. Protective effects of aliskiren and valsartan in mice with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst (2014).
116. Wang, Z., et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54, 2328-2335 (2005).
117. Shapiro, A.M., et al. International trial of the Edmonton protocol for islet transplantation. The New England journal of medicine 355, 1318-1330 (2006).
118. Sun, H., Yuan, Y. & Sun, Z.L. Cholesterol Contributes to Diabetic Nephropathy through SCAP-SREBP-2 Pathway. Int J Endocrinol 2013, 592576 (2013).
119. Inada, A., et al. A model for diabetic nephropathy: Advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocininduced diabetic mouse. Journal of Cellular Physiology 215, 383-391 (2008).
120. Tesch, G.H. & Allen, T.J. Rodent models of streptozotocin-induced diabetic nephropathy (Methods in Renal Research). Nephrology 12, 261- 266 (2007).
121. Palm, F., Ortsäter, H., Hansell, P., Liss, P. & Carlsson, P.-O. Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocindiabetic rat model. Diabetes/Metabolism Research and Reviews 20, 452- 459 (2004).
122. Tang, C., Kanter, J.E., Bornfeldt, K.E., Leboeuf, R.C. & Oram, J.F. Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys. J Lipid Res 51, 1719-1728 (2009).
123. Renard, C.B., et al. Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. The Journal of clinical investigation 114, 659-668 (2004).
124. Agarwal, R. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy. American journal of physiology. Renal physiology 290, F600-605 (2006).
125. Colhoun, H.M., et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 54, 810-819 (2009).
126. Haynes, R., et al. Effects of Lowering LDL Cholesterol on Progression of Kidney Disease. J Am Soc Nephrol (2013).
127. Cho, K.H., Kim, H.J., Kamanna, V.S. & Vaziri, N.D. Niacin improves renal lipid metabolism and slows progression in chronic kidney disease. Biochim Biophys Acta 1800, 6-15 (2009).
128. Moradi, H., Yuan, J., Ni, Z., Norris, K. & Vaziri, N.D. Reverse cholesterol transport pathway in experimental chronic renal failure. Am J Nephrol 30, 147-154 (2009).
129. Johnson, A.C., Ware, L.B., Himmelfarb, J. & Zager, R.A. HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury. Clin J Am Soc Nephrol 6, 2108-2113 (2011).
130. Zager, R.A. & Johnson, A. Renal cortical cholesterol accumulation is an integral component of the systemic stress response. Kidney Int 60, 2299- 2310 (2001).
131. Zager, R.A., Andoh, T. & Bennett, W.M. Renal cholesterol accumulation: a durable response after acute and subacute renal insults. Am J Pathol 159, 743-752 (2001).
132. Johnson, A.C., Yabu, J.M., Hanson, S., Shah, V.O. & Zager, R.A. Experimental glomerulopathy alters renal cortical cholesterol, SR-B1, ABCA1, and HMG CoA reductase expression. Am J Pathol 162, 283-291 (2003).
133. Gordon, G.B. Saturated free fatty acid toxicity. II. Lipid accumulation, ultrastructural alterations, and toxicity in mammalian cells in culture. Exp Mol Pathol 27, 262-276 (1977).
134. Gordon, G.B., Barcza, M.A. & Bush, M.E. Lipid accumulation of hypoxic tissue culture cells. Am J Pathol 88, 663-678 (1977).
135. Whitmer, J.T., Idell-Wenger, J.A., Rovetto, M.J. & Neely, J.R. Control of fatty acid metabolism in ischemic and hypoxic hearts. The Journal of biological chemistry 253, 4305-4309 (1978).
136. Aron-Wisnewsky, J., et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 56, 225- 233 (2011).
137. Bostrom, P., et al. Hypoxia converts human macrophages into triglycerideloaded foam cells. Arterioscler Thromb Vasc Biol 26, 1871-1876 (2006).
138. Byrne, C.D. Hypoxia and non-alcoholic fatty liver disease. Clin Sci (Lond) 118, 397-400 (2009).
139. Sluimer, J.C., et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol, 51, 1258-1265 (2008).
140. Cramer, T., et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112, 645-657 (2003).
141. Greijer, A.E., et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 206, 291-304 (2005).
142. Manalo, D.J., et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659-669 (2005).
143. Pouyssegur, J., Dayan, F. & Mazure, N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437-443 (2006).
144. Pugh, C.W. & Ratcliffe, P.J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9, 677-684 (2003).
145. Vengellur, A., Woods, B.G., Ryan, H.E., Johnson, R.S. & LaPres, J.J. Gene expression profiling of the hypoxia signaling pathway in hypoxiainducible factor 1alpha null mouse embryonic fibroblasts. Gene Expr 11, 181-197 (2003).
146. Wenger, R.H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 16, 1151-1162 (2002).
147. Reis, V.O., et al. The polysaccharide fraction of Propionibacterium acnes modulates the development of experimental focal segmental glomerulosclerosis. Immunobiology 217, 831-841 (2011).
148. Pereira, R.L., et al. Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis. Kidney Int 79, 1217-1227 (2011).
149. Pallottini, V., et al. Regulation of HMG-CoA reductase expression by hypoxia. J Cell Biochem 104, 701-709 (2008).
150. Rankin, E.B., et al. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol 29, 4527-4538 (2009).
151. Gimm, T., et al. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 24, 4443-4458 (2010).
152. Haase, V.H. Hypoxia-inducible factors in the kidney. American journal of physiology. Renal physiology 291, F271-281 (2006).
153. Freeburg, P.B., Robert, B., St John, P.L. & Abrahamson, D.R. Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. J Am Soc Nephrol 14, 927-938 (2003).
154. Kojima, I., et al. Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 18, 1218-1226 (2007).
155. Matsumoto, M., et al. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Am Soc Nephrol 14, 1825-1832 (2003).
156. Weidemann, A., et al. HIF activation protects from acute kidney injury. J Am Soc Nephrol 19, 486-494 (2008).
157. Singh, D.K., Winocour, P. & Farrington, K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol 4, 216-226 (2008).
158. Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog Lipid Res 52, 175-191 (2012).
159. Ma, K.L., et al. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology, 48, 770-781 (2008).
160. Gohda, T., et al. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 23, 516-524 (2012).
161. Niewczas, M.A., et al. Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol 4, 62-70 (2009).
162. Niewczas, M.A., et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 23, 507-515 (2012).
163. Zhang, G., Li, Q., Wang, L., Chen, Y. & Zhang, W. Interleukin-1beta enhances the intracellular accumulation of cholesterol by up-regulating the expression of low-density lipoprotein receptor and 3-hydroxy-3- methylglutaryl coenzyme A reductase in podocytes. Mol Cell Biochem 346, 197-204 (2011).
164. Ruan, X.Z., Varghese, Z., Powis, S.H. & Moorhead, J.F. Dysregulation of LDL receptor under the influence of inflammatory cytokines: a new pathway for foam cell formation. Kidney Int 60, 1716-1725 (2001).
165. Ruan, X.Z., et al. PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway. J Am Soc Nephrol 14, 593-600 (2003).
166. Chen, Y., et al. Inflammatory cytokines disrupt LDL-receptor feedback regulation and cause statin resistance: a comparative study in human hepatic cells and mesangial cells. American journal of physiology. Renal physiology 293, F680-687 (2007).
167. Bakker, P.J., et al. Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation. Kidney Int 85, 1112-1122 (2014).