title: Transforming growth factor-beta1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins: a central pathway in progressive glomerulosclerosis.
abstract: Chronic diseases of the kidney have a progressive course toward organ failure. Common pathway mechanisms of progressive injury, irrespectively of the etiology of the underlying diseases, include glomerular capillary hypertension and enhanced passage of plasma proteins across the glomerular capillary barrier because of impaired permselective function. These changes are associated with podocyte injury and glomerular sclerosis. Direct evidence for causal roles is lacking, particularly for the link between intraglomerular protein deposition and sclerosing reaction. Because transforming growth factor-beta1 (TGF-beta1) is the putative central mediator of scarring, we hypothesized that TGF-beta1 can be up-regulated by protein overload of podocytes thereby contributing to sclerosis. In rats with renal mass reduction, protein accumulation in podocytes as a consequence of enhanced transcapillary passage preceded podocyte dedifferentiation and injury, increase in TGF-beta1 expression in podocytes, and TGF-beta1-dependent activation of mesangial cells. Angiotensin-converting enzyme inhibitor prevented both accumulation of plasma proteins and TGF-beta1 overexpression in podocytes and sclerosis. Albumin load on podocytes in vitro caused loss of the synaptopodin differentiation marker and enhanced TGF-beta1 mRNA and protein. Conditioned medium of albumin-stimulated podocytes induced a sclerosing phenotype in mesangial cells, an effect mimicked by TGF-beta1 and blocked by anti-TGF-beta1 antibodies. Thus, the passage of excess plasma proteins across the glomerular capillary wall is the trigger of podocyte dysfunction and of a TGF-beta1-mediated mechanism underlying sclerosis. Agents to reduce TGF-beta1, possibly combined with angiotensin blockade, should have priority in novel approaches to treatment of progressive nephropathies.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. abbate@marionegri.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Stefania
authors.initials: S
authors.lastname: Angioletti
authors.forename: Susanna
authors.initials: S
authors.lastname: Tomasoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Zanchi
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000601:surgery; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017706:Lisinopril / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012598:Sclerosis / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001798:Blood Proteins; D003893:Desmin; D008840:Microfilament Proteins; C503967:SYNPO protein, human; C503968:Synpo protein, mouse; C503969:Synpo protein, rat; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017706:Lisinopril