TUBULOINTERSTITIAL RESPONSES IN THE PROGRESSION OF GLOMERULAR-DISEASES - ALBUMINURIA MODULATES ALPHA(V)BETA(5) INTEGRIN

Proteinuria represents one of the most unfavorable prognostic factors in the progression of nephropathies. Several lines of evidence support a role for proteinuria pei se in the development of interstitial fibr osis, albeit the molecular mechanisms are still unknown. We investigat ed the potential role of integrins expressed on tubular cells in regul ating the synthesis and organization of interstitial matrix or as medi ators of tubulointerstitial damage in conditions mimick ing the nephro tic milieu. Under basal conditions. cultured tubular cells highly expr essed alpha(3) beta(1) and, at focal contacts, alpha(v) beta(3). In co ntrast, alpha(v) beta(5), was weakly and diffusely distributed all ove r the plasma membrane. Cultures on a variety of matrix substrates (fib ronectin, laminin, collagen types I and IV, vitronectin, von Willebran d factor, fibrinogen) did not induce any phenotypic change in integrin expression by tubular cells. Conversely, the addition of albumin resu lted in a highly increased membrane expression of beta(5), which was o rganized in typical focal contacts and was related to the dose of albu min added. Immunofluorescence, flow cytometry, immunoprecipitation and RT-PCR experiments argue for a complex mechanism that includes increa sed post-transcriptionally regulated protein synthesis, accelerated co nversion of precursors to mature forms, and increased surface delivery to discrete adhesive structures. Up-regulation of the beta(5), chain in tubular cells was confirmed in 9 out of 11 kidney biopsies from pro teinuric glomerulonephritides including membranous and focal sclerosin g glomerulonephritis, while it was not expressed in nonproteinuric kid neys including five biopsy specimens. This is the first report indicat ing that proteinuria up-regulates the surface expression and distribut ion of a specific integrin chain on tubular cells. These observations suggest the participation of integrins in a hitherto unexplored mechan ism of tubulointerstitial responses to glomerular injury.