Abrogation of protein uptake through megalin-deficient proximal tubules does not safeguard against tubulointerstitial injury.
Sustained proteinuria and tubulointerstitial damage have been closely linked with progressive renal failure. Upon excess protein endocytosis, tubular epithelial cells are thought to produce mediators that promote inflammation, tubular degeneration, and fibrosis. This concept was tested in a transgenic mouse model with megalin deficiency. Application of an anti-glomerular basement membrane serum to transgenic megalin-deficient mice [Cre(+)/GN] and megalin-positive littermates [Cre(-)/GN] produced the typical glomerulonephritis (GN) with heavy proteinuria in both groups. Tubulointerstitial damages correlated closely with glomerular damages in pooled Cre(+)/GN and Cre(-)/GN mice. Owing to a mosaic pattern of megalin expression in the mutant mice, Cre(+)/GN kidneys permitted side-by-side analysis of megalin-deficient and megalin-positive tubules in the same kidney. Protein endocytosis was found only in megalin-positive cells. TGF-beta, intercellular adhesion molecule, vascular cellular adhesion molecule, endothelin-1, and cell proliferation were high in megalin-positive cells, whereas apoptosis, heat-shock protein 25, and osteopontin were enhanced in megalin-deficient cells. No fibrotic changes were associated with either phenotype. Tubular degeneration with interstitial inflammation was found only in nephrons with extensive crescentic lesions at the glomerulotubular junction. In sum, enhanced protein endocytosis indeed led to an upregulation of profibrotic mediators in a megalin-dependent way; however, there was no evidence that endocytosis played a pathogenetic role in the development of the tubulointerstitial disease.
Theilig
Franziska
F
Institut für Vegetative Anatomie, Charité Universitätsmedizin Berlin, Philippstrasse 12, 10115 Berlin.
Kriz
Wilhelm
W
Jerichow
Timo
T
Schrade
Petra
P
Hähnel
Brunhilde
B
Willnow
Thomas
T
Le Hir
Michel
M
Bachmann
Sebastian
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D018832:Molecular Chaperones; D009030:Mosaicism; D009363:Neoplasm Proteins / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D053495:Osteopontin / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D019010:Vascular Cell Adhesion Molecule-1; D053495:Osteopontin; D018799:Intercellular Adhesion Molecule-1