Clinical Investigation

Kidney International (1993) 44, 1341–1351; doi:10.1038/ki.1993.387

Receptor-mediated uptake of IDL and LDL from nephrotic patients by glomerular epithelial cells

Annette Krämer1, Matthias Nauck1, Hermann Pavenstädt1, Susanne Schwedler1, Heinrich Wieland1, Peter Schollmeyer1 and Christoph Wanner1

1Department of Medicine, Divisions of Nephrology and Clinical Chemistry, University of Freiburg, Germany

Correspondence: Christoph Wanner MD, Department of Medicine, Division of Nephrology, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany.

Received 2 March 1993; Revised 16 July 1993; Accepted 19 July 1993.

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Abstract

Receptor-mediated uptake of IDL and LDL from nephrotic patients by glomerular epithelial cells. Although hyperlipidemia is a well-recognized complication of the nephrotic syndrome, the precise interaction of human glomerular cells and human lipoproteins, abnormal in lipid and protein composition, has not been clearly defined. This study examines receptor mediated binding, internalization and degradation as well as intracellular cholesterol metabolism of apoB-100 containing LDL and apoB,E containing IDL, isolated from patients with the nephrotic syndrome (N = 6), in human glomerular epithelial cells and skin fibroblasts. In the patients, serum LDL cholesterol level was increased threefold and IDL elevenfold as compared to healthy subjects. IDL of nephrotic patients contained 72% more cholesterol than IDL of healthy controls. No difference in lipid/protein composition was found in the LDL density range. Therefore, nephrotic and control LDL showed identical affinities for receptor mediated binding, internalization and degradation. Furthermore, inhibition of intracellular sterol synthesis and cholesteryl ester formation after incubation with LDL was comparable. In contrast, cholesterol-rich IDL of nephrotic patients was taken up by glomerular epithelial cells with higher affinity than LDL and control IDL, as well as intracellular sterol synthesis was suppressed more effectively than by control IDL. The cholesterol esterification rate of IDL from patients was enhanced 3.5-fold as compared to control IDL. In comparison to fibroblasts, glomerular epithelial cells showed about 15% of the maximal capacity for LDL uptake, but 31% for IDL from nephrotic patients. The data indicate that hypercholesterolemia of nephrotic origin cannot be explained by reduced ligand binding for LDL. ApoE containing IDL, which accumulate in nephrotic patients, were avidly taken up by glomerular epithelial cells via receptor dependent pathway. These lipoproteins could therefore play the predominant role in glomerular lipid accumulation and development of glomerulosclerosis.

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References

  1. Joven J, Villabona C, Villella E, Masana L, Alberti R, Valles M: Abnormalities of lipoproteins metabolism in patients with the nephrotic syndrome. N Engl J Med 323:579–584, 1990 | PubMed | ISI | ChemPort |
  2. Gherardi E, Rota E, Calandra S, Genova R, Tamborino A: Relationship among the concentrations of serum lipoproteins and changes in their chemical composition in patients with untreated nephrotic syndrome. Eur J Clin Invest 7:563–570, 1977 | PubMed | ISI | ChemPort |
  3. Wanner C, Böhler J, Eckardt HG, Wieland H, Schollmeyer P: Effect of simvastatin on lipoprotein(a) and lipoprotein composition in patients with nephrotic syndrome. Clin Nephrol (in press)
  4. Muls E, Rosseneu M, Daniels R: Lipoproteins distribution and composition in the human nephrotic syndrome. Atherosclerosis 54:225–230, 1985 | Article | PubMed | ISI | ChemPort |
  5. Marsh JB: Lipoprotein metabolism in experimental nephrosis. J Lipid Res 25:1619–1623, 1984 | PubMed | ISI | ChemPort |
  6. Staprans I, Felts JM, Couser WG: Glycosaminoglycans and chylomicron metabolism in control and nephrotic rats. Metabolism 36:496–501, 1987 | Article | PubMed | ISI | ChemPort |
  7. Warwick GL, Packard CJ, Demant T, Bedford DK, Boulton-Jones M, Shepherd J: Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria. Kidney Int 40:129–138, 1991 | PubMed | ISI | ChemPort |
  8. Schönholzer KW, Waldron M, Magil AB: Intraglomerular foam cells and human focal glomerulosclerosis. Nephron 62:130–136, 1992 | PubMed | ISI | ChemPort |
  9. Moorhead JF, Chan MK, El-Nahas M, Varghese Z: Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancet ii:1309–1311, 1982
  10. Diamond JR, Karnowski MJ: Focal and segmental glomerulosclerosis: Analogies to atherosclerosis. Kidney Int 33:917–924, 1988 | PubMed | ISI | ChemPort |
  11. Keane WF, Kasiske BL, O'Donnell MP: Lipids and progressive glomerulosclerosis. A model analogous to atherosclerosis. Am J Nephrol 8:261–271, 1988 | PubMed | ISI | ChemPort |
  12. Schmitz PG, Kasiske BL, O'Donnell MP, Keane WF: Lipids and progressive renal injury. Semin Nephrol 9:354–369, 1989 | PubMed | ISI | ChemPort |
  13. Olivetti G, Anversa P, Melissari M, Loud AV: Morphometry of the renal corpuscle during postnatal growth and compensatory hypertrophy. Kidney Int 17:438–454, 1980 | PubMed | ChemPort |
  14. Gröne HJ, Walli AK, Gröne E, Krämer A, Clemens MR, Seidel D: Receptor mediated uptake of apo E and apo B rich lipoproteins by human glomerular epithelial cells. Kidney Int 37:1449–1459, 1990 | PubMed | ISI | ChemPort |
  15. Pavenstädt H, Späth M, Schlunck G, Nauck M, Fischer R, Wanner C, Schollmeyer P: Effect of nucleotides on the cytosolic free calcium activity and inositol phosphate formation in human glomerular epithelial cells. Br J Pharmacol 107:189–195, 1992 | PubMed | ChemPort |
  16. Nosaka K, Nishi R, Imaki H, Suzuki K, Kuwata S, Noiri E, Aizawa C, Kurokawa K: Permeable type I collagen membrane promotes glomerular epithelial cell growth in culture. Kidney Int 43:470–478, 1993 | PubMed | ChemPort |
  17. Gilbert SF, Migeon R: D-valine as a selective agent for normal human and rodent epithelial cells in culture. Cell 5:11–17, 1975 | Article | PubMed | ISI | ChemPort |
  18. Kreisberg JI, Karnowski MJ: Glomerular cells in culture. Kidney Int 23:439–447, 1983 | PubMed | ISI | ChemPort |
  19. Bross KJ, Pangalis GA, Staatz CG, Blume KG: Demonstration of cell surface antigens and their antibodies by the peroxidase-antiperoxidase method. Transplantation 25:331–334, 1978
  20. Cybulsky AV, Carbonetto S, Huang Q, McTavish AJ, Cyr M-D: Adhesion of rat glomerular epithelial cells to extracellular matrices: Role of integrins. Kidney Int 42:1099–1106, 1992 | PubMed | ISI | ChemPort |
  21. Camussi G, Mariano F, Biancone L, Montrucchio G, Vercellone A: Effect of cytokines on the cytoskeleton of resident glomerular cells. Kidney Int 43(Suppl 39):S32–S36, 1993 | ISI | ChemPort |
  22. Holthöfer H, Saino K, Miettinen P: Rat glomerular cells do not express podocytic markers when cultured in vitro. Lab Invest 65:548–557, 1991 | PubMed | ISI | ChemPort |
  23. Delarue F, Virone A, Hagege J, Lacave R, Peraldo M-N, Adida C, Rondeau E, Feuneun J, Sraer J-D: Stable cell line of T-SV40 immortalized human glomerular visceral epithelial cells. Kidney Int 40:906–912, 1991 | PubMed | ISI | ChemPort |
  24. Manual of Laboratory Operation: Lipid Research Clinics Program. DHEW No (NIH) 75-628 Bethesda, National Heart and Lung Institute, 1974, pp. 1–74
  25. Wanner C, Hörl WH, Luley C, Wieland H: Effect of HMGCoA reductase inhibitors in hypercholesterolemic patients on hemodialysis. Kidney Int 39:754–760, 1991 | PubMed | ISI | ChemPort |
  26. Luley C, Baumstark MW, Wieland H: Rapid apolipoprotein E phenotyping by immunofixation in agarose. J Lipid Res 32:880–883, 1991
  27. Maguire GF, Lee M, Connelly PW: Sodium dodecyl sulfate-glycerol polyacrylamide slab gel electrophoresis for the resolution of apolipoproteins. J Lipid Res 30:757–761, 1989
  28. Havel RJ, Eder HA, Bragdon JH: The distribution and chemical composition of ultracentrifugally separated lipoproteins in human plasma. J Clin Invest 34:1345–1353, 1955 | PubMed | ISI | ChemPort |
  29. McFarlane AS: Efficient trace labelling of proteins with iodine. Nature 182:53–56, 1958 | PubMed | ISI | ChemPort |
  30. Bilheimer DW, Eisenberg S, Levy RI: The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta 260:212–221, 1972 | Article | PubMed | ISI | ChemPort |
  31. Goldstein JL, Kita T, Brown MS: Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med 309:288–296, 1983
  32. Goldstein JL, Basu JK, Brown US: Receptor-mediated endocytosis of low density lipoprotein in cultured cells, in Methods in Enzymology (Vol 98), edited by Fischer S, Fleischer B, New York, Academic Press Inc., 1983, pp. 241–260
  33. Dullaart RPF, Gansevoort RT, Dikkeschei BD, de Zeeuw D, de Jong PE, van Tol A: Role of elevated lecithin: Cholesterol acyltransferase and cholesteryl ester transfer protein activities in abnormal lipoproteins from proteinuric patients. Kidney Int 44:91–97, 1993 | PubMed | ISI | ChemPort |
  34. Davies RW, Staprans I, Hutchison FN, Kaysen GA: Proteinuria, not altered albumin metabolism, affects hyperlipidemia in the nephrotic rat. J Clin Invest 86:500–505, 1990
  35. Joven J, Masana L, Villabona C, Vilella E, Bargallo T, Trias M, Figueras M, Turner PR: Low density lipoprotein metabolism in rats with puromycin aminonucleoside-induced nephrotic syndrome. Metabolism 38:491–495, 1989
  36. Grundy SM, Vega GL: Cause of high blood cholesterol. Circulation 81:412–427, 1990 | PubMed |
  37. Kowal C, Herz J, Goldstein HL, Esser V, Brown MS: Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apo-E-enriched lipoproteins. Proc Natl Acad Sci USA 86:5810–5814, 1989

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