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 language | English |
|---|---|
| Pages (from-to) | 2179-2193 |
| Number of pages | 15 |
| Journal | American Journal of Pathology |
| Volume | 161 |
| Issue number | 6 |
| Publication status | Published - Dec 1 2002 |
Fingerprint
ASJC Scopus subject areas
- Pathology and Forensic Medicine
Cite this
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 journal › Article
}
TY - JOUR
T1 - Transforming growth factor-β1 is up-regulated by podocytes in response to excess intraglomerular passage of proteins
T2 - A central pathway in progressive glomerulosclerosis
AU - Abbate, Mauro
AU - Zoja, Carla
AU - Morigi, Marina
AU - Rottoli, Daniela
AU - Angioletti, Stefania
AU - Tomasoni, Susanna
AU - Zanchi, Cristina
AU - Longaretti, Lorena
AU - Donadelli, Roberta
AU - Remuzzi, Giuseppe
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=17644444238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=17644444238&partnerID=8YFLogxK
M3 - Article
C2 - 12466133
AN - SCOPUS:17644444238
VL - 161
SP - 2179
EP - 2193
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -