Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting a wound healing response as a consequence of infarction. In the kidney, chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and finally interstitial fibrosis/tubular atrophy (IF/TA). Compared to this glomerulus-induced focal replacement scar, diffuse fibrosis independent of tubular atrophy appears to be a different pathogenic process. Kidney fibrosis appears to develop in a compartment-specific manner, but whether focal and diffuse fibrosis has distinct characteristics associated with other glomerular or tubulointerstitial lesions remains elusive. In the present study, we aimed to analyze renal fibrotic patterns related to renal lesions, which directly contribute to renal fibrogenesis, to unravel fibrotic patterns and manifestations upon damage to distinct renal compartments. Patterns of kidney fibrosis were analyzed in experimental models of CKD and various renal pathologies in correlation with histopathological and ultrastructural findings. After the induction of isolated crescentic glomerulonephritis (GN) in nephrotoxic serum-nephritis (NTN), chronic glomerular damage resulted in predominantly focal fibrosis adjacent to atrophic tubules. By contrast, using unilateral ureteral obstruction (UUO) as a model of primary injury to the tubulointerstitial compartment revealed diffuse fibrosis as the predominant pattern of chronic lesions. Finally, folic acid-induced nephropathy (FAN) as a model of primary tubular injury with consecutive tubular atrophy independent of chronic glomerular damage equally induced predominant focal IF/TA. By analyzing several renal pathologies, our data also suggest that focal and diffuse fibrosis appear to contribute as chronic lesions in the majority of human renal disease, mainly being present in antineutrophil cytoplasmic antibody (ANCA)-associated GN, lupus nephritis, and IgA nephropathy (IgAN). Focal IF/TA correlated with glomerular damage and irreversible injury to nephrons, whereas diffuse fibrosis in ANCA GN was associated explicitly with interstitial inflammation independent of glomerular damage and nephron loss. Ultrastructural analysis of focal IF/TA versus diffuse fibrosis revealed distinct matrix compositions, further supported by different collagen signatures in transcriptome datasets. With regard to long-term renal outcome, only the extent of focal IF/TA correlated with the development of end-stage kidney disease (ESKD) in ANCA GN. In contrast, diffuse kidney fibrosis did not associate with the long-term renal outcome. In conclusion, we here provide evidence that a focal pattern of kidney fibrosis seems to be associated with nephron loss and replacement scarring. In contrast, a diffuse pattern of kidney fibrosis appears to result from primary interstitial inflammation and injury.
Background and Aims Plasmalemmal vesicle-associated protein-1 (PLVAP or PV-1) is a major protein of diaphragm-bridged fenestrated endothelial cells found in capillaries of neuroendocrine glands and peritubular capillaries. In contrast to peritubular capillaries, the glomerulus is known for its unique fenestrated endothelium without any diaphragm formation thereby ensuring free filtration. Here we aimed to investigate whether PLVAP is expressed in glomerular endothelial cells in various glomerular diseases and whether PLVAP expression is associated with the formation of diaphragm-bridged endothelial cells. Method A total number of 114 biopsy samples of glomerular diseases including diabetic nephropathy, FSGS, IgA-Nephritis, ANCA-GN and Lupus–Nephritis were analyzed immunohistochemistically for glomerular PLVAP expression. A fraction of PLVAP positive cases was subsequently investigated ultrastrucurally for the formation of diaphragm-bridged glomerular endothelial cells. Results One third of all cases showed at least one glomerulus with one single circumferential PLVAP staining. Interestingly, the most prominent staining, affecting the entire glomerular tuft, was observed in diabetic nephropathy and ANCA-GN. Ultrastructurally, such cases exhibited injured endothelium with focal detachment from the glomerular basement membrane, loss of pore formation and frequently diaphragm-bridged fenestrations reminiscent of peritubular capillaries. Conclusion Our data show that injured glomerular endothelium is capable of forming true diaphragm-bridged fenestrations, suggesting a possible role in preventing glomerular protein leakage and limiting its detachment from the GBM.
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