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 per se in the development of interstitial fibrosis, albeit the molecular mechanisms are still unknown. We investigated the potential role of integrins expressed on tubular cells in regulating the synthesis and organization of interstitial matrix or as mediators of tubulointerstitial damage in conditions mimicking the nephrotic milieu. Under basal conditions, cultured tubular cells highly expressed alpha 3 beta 1 and, at focal contacts, alpha v beta 3. In contrast, alpha v beta 5 was weakly and diffusely distributed all over the plasma membrane. Cultures on a variety of matrix substrates (fibronectin, laminin, collagen types I and IV, vitronectin, von Willebrand factor, fibrinogen) did not induce any phenotypic change in integrin expression by tubular cells. Conversely, the addition of albumin resulted in a highly increased membrane expression of beta 5, which was organized in typical focal contacts and was related to the dose of albumin added. Immunofluorescence, flow cytometry, immunoprecipitation and RT-PCR experiments argue for a complex mechanism that includes increased post-transcriptionally regulated protein synthesis, accelerated conversion 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 proteinuric glomerulonephritides including membranous and focal sclerosing glomerulonephritis, while it was not expressed in nonproteinuric kidneys including five biopsy specimens. This is the first report indicating that proteinuria up-regulates the surface expression and distribution of a specific integrin chain on tubular cells. These observations suggest the participation of integrins in a hitherto unexplored mechanism of tubulo-interstitial responses to glomerular injury.
Peruzzi
L
L
Division of Nephrology and Dialysis, University of Torino, Regina Margherita Children's Hospital, Italy.
Trusolino
L
L
Amore
A
A
Gianoglio
B
B
Cirina
P
P
Basso
G
G
Emancipator
S N
SN
Marchisio
P C
PC
Coppo
R
R
D000419:Albuminuria / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D001706:Biopsy; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D017403:In Situ Hybridization; D039564:Integrin alphaV; D039641:Integrin beta Chains; D016023:Integrins / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009404:Nephrotic Syndrome / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism*; D013997:Time Factors
D015703:Antigens, CD; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D007074:Immunoglobulin G; D039564:Integrin alphaV; D039641:Integrin beta Chains; D016023:Integrins; D008070:Lipopolysaccharides; C084344:integrin beta5