Transforming growth factor-β1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins: A central pathway in progressive glomerulosclerosis

Mauro Abbate, Carla Zoja, Marina Morigi, Daniela Rottoli, Stefania Angioletti, Susanna Tomasoni, Cristina Zanchi, Lorena Longaretti, Roberta Donadelli, Giuseppe Remuzzi

Research output: Contribution to journalArticle

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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-β1 (TGF-β1) is the putative central mediator of scarring, we hypothesized that TGF-β1 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-β1 expression in podocytes, and TGF-β1-dependent activation of mesangial cells. Angiotensin-converting enzyme inhibitor prevented both accumulation of plasma proteins and TGF-β1 overexpression in podocytes and sclerosis. Albumin load on podocytes in vitro caused loss of the synaptopodin differentiation marker and enhanced TGF-β1 mRNA and protein. Conditioned medium of albumin-stimulated podocytes induced a sclerosing phenotype in mesangial cells, an effect mimicked by TGF-β1 and blocked by anti-TGF-β1 antibodies. Thus, the passage of excess plasma proteins across the glomerular capillary wall is the trigger of podocyte dysfunction and of a TGF-beta;1-mediated mechanism underlying sclerosis. Agents to reduce TGF-β1, possibly combined with angiotensin blockade, should have priority in novel approaches to treatment of progressive nephropathies.

Original languageEnglish
Pages (from-to)2179-2193
Number of pages15
JournalAmerican Journal of Pathology
Volume161
Issue number6
Publication statusPublished - Dec 1 2002

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Podocytes
Staphylococcal Protein A
Transforming Growth Factors
Sclerosis
Blood Proteins
Mesangial Cells
Albumins
Wounds and Injuries
Proteins
Differentiation Antigens
Angiotensins
Conditioned Culture Medium
Chronic Renal Insufficiency
Angiotensin-Converting Enzyme Inhibitors
Transforming Growth Factor beta
Cicatrix
Hypertension
Phenotype
Kidney
Messenger RNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Transforming growth factor-β1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins : A central pathway in progressive glomerulosclerosis. / Abbate, Mauro; Zoja, Carla; Morigi, Marina; Rottoli, Daniela; Angioletti, Stefania; Tomasoni, Susanna; Zanchi, Cristina; Longaretti, Lorena; Donadelli, Roberta; Remuzzi, Giuseppe.

In: American Journal of Pathology, Vol. 161, No. 6, 01.12.2002, p. 2179-2193.

Research output: Contribution to journalArticle

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