Following specific podocyte injury captopril protects against progressive long term renal damage

Background: Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model. Methods: We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group. Results: After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05). Conclusions: Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury

Padiglione nello spazio incontri del carcere di Bollate

Sembra fatta d'aria e ha un forte significato simbolico questa casetta pensata per gli incontri tra i detenuti e i loro bambini. A Milano, nel carcere di Bollat

A Bollate un progetto simbolico

Sembra fatta di aria e ha un forte significato simbolico questa casetta pensata per gli incontri tra i detenuti e i loro bambini. A Milano, nel carcere di Bollat

Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease

Background/Aims: Experimental and clinical evidence suggested that monocyte chemoattractant protein-1 (MCP-1/CCL2) has a role in the development of interstitial inflammation and renal failure in polycystic kidney disease (PKD). We investigated whether bindarit, an inhibitor of MCP-1/CCL2 synthesis, could influence the evolution of PKD in PCK rats. Methods: PCK rats were treated from 5 to 15 weeks of age with vehicle or bindarit. Sprague-Dawley rats served as control. For in vitro studies, murine podocytes were exposed to albumin with or without bindarit. Results: MCP-1 mRNA was upregulated in the kidney of PCK rats and reduced by bindarit. Treatment limited overexpression of MCP-1 protein by epithelial cells of dilated tubules and cysts, and interstitial inflammatory cells. Excessive renal accumulation of mono-cytes/macrophages was lowered by bindarit by 41%. Serum creatinine slightly increased in PCK rats on vehicle and was similar to controls after bindarit. Kidney and liver cysts were not affected by treatment. Bindarit significantly reduced progressive proteinuria of PCK rats. The antiproteinuric effect was associated with the restoration of the defective nephrin expression in podocytes of PCK rats. Bindarit limited podocyte foot process effacement and ameliorated slit diaphragm frequency. In cultured podocytes, bindarit reduced MCP-1 production in response to albumin and inhibited albumin-induced cytoskeletal remodeling and cell migration. Conclusion: This study showed that although bindarit did not prevent renal cyst growth, it limited interstitial inflammation and renal dysfunction and reduced proteinuria in PKD. Thus, bindarit could be considered a therapeutic intervention complementary to therapies specifically acting to block renal cyst growth

Old and new targets for innovative antimalarial compounds: the different strategies of the Italian Malaria Network

35nonenoneBASILICO N; BOSISIO E; BUELLI F; CAMPIANI G; CASAGRANDE M; CASTELLI F; COGHI P; CORBETT Y; CORTALEZZI L; D'ALESSANDRO U; DELL'AGLI M; ESPOSITO F; FATTORUSSO C; FATTORUSOO E; FINAURINI S; GALLI G.V; GEMMA S; HABLUETZEL A; LUCANTONI L; MELATO S; MONTI D; OLLIARO P; OMODEO-SALÉ F; PARAPINI S; PERSICO M; RIZZI M; ROMEO S; ROSSI F; RUSCONI C; SPARATORE A; TAGLIALATELA SCAFATI O; VAN DER BOOGART E; TARAMELLI D; VAIATA M; YERBANGA SBasilico, N; Bosisio, E; Buelli, F; Campiani, G; Casagrande, M; Castelli, Francesco; Coghi, P; Corbett, Y; Cortalezzi, L; D'Alessandro, U; Dell'Agli, M; Esposito, F; Fattorusso, C; Fattorusoo, E; Finaurini, S; GALLI G., V; Gemma, S; Habluetzel, A; Lucantoni, L; Melato, S; Monti, D; Olliaro, P; OMODEO SALÉ, F; Parapini, S; Persico, M; Rizzi, M; Romeo, S; Rossi, F; Rusconi, C; Sparatore, A; TAGLIALATELA SCAFATI, O; VAN DER BOOGART, E; Taramelli, D; Vaiata, M; Yerbanga, S

Old and new targets for innovative antimalarial compounds : the different strategies of the Italian Malaria Network

Clinical treatment-failures to affordable drugs encouraged new investigation for discovery and development of new prophylactic and therapeutic interventions against malaria. The Drug Discovery Cluster (DDcl) of the Italian Malaria Network gathers several highly integrated and complementary laboratories from different Italian Institutions to identify, synthesise, screen in vitro and in vivo new antimalarial molecules directed against the intraerythrocytic stage of P. falciparum parasites and/or with transmission blocking activity to select lead compounds for further development. Complementary research activities, both in vitro and in the clinics, aim at investigating the pathogenetic mechanisms of severe malaria anaemia and the different manifestations of the disease in malaria-HIV co-infected patients to identify new therapies and improve survival.Clinical treatment-failures to affordable drugs encouraged new investigation for discovery and development of new prophylactic and therapeutic interventions against malaria. The Drug Discovery Cluster (DDcl) of the Italian Malaria Network gathers several highly integrated and complementary laboratories from different Italian Institutions to identify, synthesise, screen in vitro and in vivo new antimalarial molecules directed against the intraerythrocytic stage of P. falciparum parasites and/or with transmission blocking activity to select lead compounds for further development. Complementary research activities, both in vitro and in the clinics, aim at investigating the pathogenetic mechanisms of severe malaria anaemia and the different manifestations of the disease in malaria-HIV co-infected patients to identify new therapies and improve survival