Glomerular diseases remain the most common cause of progressive renal failure that may require dialysis or kidney transplantation. Many forms of renal disease such as IgA nephropathy, lupus nephritis and diabetic nephropathy, progress to renal failure and are characterised histologically by mesangial cell proliferation and accumulation of mesangial matrix. Mesangial cells (MC) play an active part in the inflammatory response to glomerular injury. MC, produce, and respond to, a variety of cytokines and growth factors, and regulate the turnover of extracellular matrix. There are evidences that glomerular expression of MCP-1 correlates with the degree of renal damage, playing a major role in the pathogenesis of renal diseases (Viedt&Orth, 2002). Bindarit, 2-methyl-2-[[1-(phenylmethyl)-1H-indazol-3-yl]methoxy]propanoic acid, is an original indazolic derivative able to inhibit the synthesis of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2, MCP-3/CCL7, MCP-2/CCL8) (Mirolo et al., 2008) and it has been demonstrated able to decrease MCP-1 urinary excretion and albuminuria in patients with Lupus Nephritis. However, the mechanism by which bindarit decreases proteinuria has not been elucidated yet, so the aim of this work was to elucidate the effect of MCP-1 synthesis inhibition on in vitro models of mesangial cell dysfunction. Firstly, the effect of bindarit on MCP-1 release by human renal mesangial cells (HRMCs) in response to angiotensin II (AngII) and endothelin I (ET1) was investigated by means of ELISA. ET1 and AngII significantly stimulated MCP-1 release by HRMCs after 6-12h stimulation. Bindarit (10-300mM) significantly inhibited MCP-1 release in response to AngII and ET1 within 12h. In addition, mRNA MCP-1 expression in ET1-stimulated cells was also inhibited by bindarit, confirming an effect of the drug at transcriptional level. Mesangial cells exposed to ET1 showed a significant increase of mRNA collagen IV expression, which was significantly inhibited by bindarit. Moreover, since mesangial cell growth is a hallmark of many progressive renal diseases, the effect of bindarit on HRMC proliferation was investigated. Bindarit significantly and concentration-dependently inhibited HRMCs proliferation in response to ETI and AngII. These data support an important role of MCP-1 synthesis in mesangial cell dysfunction and suggest the therapeutic potential of MCPs inhibitors in progressive renal disease.
Effect of bindarit, a MCPs synthesis inhibitor, on mesangial cell dysfunction / S. Paccosi; C. Musilli; A. Mugelli; A. Guglielmotti; A. Parenti. - ELETTRONICO. - (2011), pp. 0-0. (Intervento presentato al convegno 35° CONGRESSO NAZIONALE DELLA SOCIETà ITALIANA DI FARMACOLOGIA IL FARMACO: DALLA RICERCA ALLA SALUTE DELL'UOMO tenutosi a BOLOGNA nel 14-17/09/2011).
Effect of bindarit, a MCPs synthesis inhibitor, on mesangial cell dysfunction
PACCOSI, SARA;MUSILLI, CLAUDIA;MUGELLI, ALESSANDRO;PARENTI, ASTRID
2011
Abstract
Glomerular diseases remain the most common cause of progressive renal failure that may require dialysis or kidney transplantation. Many forms of renal disease such as IgA nephropathy, lupus nephritis and diabetic nephropathy, progress to renal failure and are characterised histologically by mesangial cell proliferation and accumulation of mesangial matrix. Mesangial cells (MC) play an active part in the inflammatory response to glomerular injury. MC, produce, and respond to, a variety of cytokines and growth factors, and regulate the turnover of extracellular matrix. There are evidences that glomerular expression of MCP-1 correlates with the degree of renal damage, playing a major role in the pathogenesis of renal diseases (Viedt&Orth, 2002). Bindarit, 2-methyl-2-[[1-(phenylmethyl)-1H-indazol-3-yl]methoxy]propanoic acid, is an original indazolic derivative able to inhibit the synthesis of the monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-1/CCL2, MCP-3/CCL7, MCP-2/CCL8) (Mirolo et al., 2008) and it has been demonstrated able to decrease MCP-1 urinary excretion and albuminuria in patients with Lupus Nephritis. However, the mechanism by which bindarit decreases proteinuria has not been elucidated yet, so the aim of this work was to elucidate the effect of MCP-1 synthesis inhibition on in vitro models of mesangial cell dysfunction. Firstly, the effect of bindarit on MCP-1 release by human renal mesangial cells (HRMCs) in response to angiotensin II (AngII) and endothelin I (ET1) was investigated by means of ELISA. ET1 and AngII significantly stimulated MCP-1 release by HRMCs after 6-12h stimulation. Bindarit (10-300mM) significantly inhibited MCP-1 release in response to AngII and ET1 within 12h. In addition, mRNA MCP-1 expression in ET1-stimulated cells was also inhibited by bindarit, confirming an effect of the drug at transcriptional level. Mesangial cells exposed to ET1 showed a significant increase of mRNA collagen IV expression, which was significantly inhibited by bindarit. Moreover, since mesangial cell growth is a hallmark of many progressive renal diseases, the effect of bindarit on HRMC proliferation was investigated. Bindarit significantly and concentration-dependently inhibited HRMCs proliferation in response to ETI and AngII. These data support an important role of MCP-1 synthesis in mesangial cell dysfunction and suggest the therapeutic potential of MCPs inhibitors in progressive renal disease.
I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
