IN PROGRESSIVE NEPHROPATHIES, OVERLOAD OF TUBULAR CELLS WITH FILTEREDPROTEINS TRANSLATES GLOMERULAR-PERMEABILITY DYSFUNCTION INTO CELLULARSIGNALS 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 i nsult. Progressive glomerulopathies have in common persistently high l evels of urinary protein excretion and tubulointerstitial lesions at b iopsy. Among the cellular mechanisms that may determine progression re gardless of etiology, the traffic of excess proteins filtered from glo merulus in renal tubule may have functional importance by initiating i nterstitial inflammation in the early phase of parenchymal injury. Thi s study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of protein uric 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-posi tive 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 (passiv e Heymann nephritis), indicating that the interstitial inflammatory re action develops at the sites of protein overload, regardless of the ty pe of glomerular injury. Osteopontin was detectable in cells of proxim al tubules congested with protein in both models at sites of interstit ial 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 candid ate process translating glomerular protein leakage into cellular signa ls of interstitial inflammation. Mechanisms underlying the proinflamma tory 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.