In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.
Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.
Abbate
M
M
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Zoja
C
C
Corna
D
D
Capitanio
M
M
Bertani
T
T
Remuzzi
G
G
D000418:Albumins / Q000032:analysis*; D000818:Animals; D002463:Cell Membrane Permeability; D004195:Disease Models, Animal; D018450:Disease Progression; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000000981:diagnostic imaging; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000648:ultrastructure*; D008297:Male; D016253:Microscopy, Immunoelectron; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology*; D053495:Osteopontin; D010750:Phosphoproteins / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D014463:Ultrasonography
D000418:Albumins; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D010750:Phosphoproteins; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin