Calpains contribute to vascular repair in rapidly progressive form of glomerulonephritis: potential role of their externalization.

OBJECTIVE: Calpains, calcium-activated proteases, mediate the angiogenic signals of vascular endothelial growth factor. However, their involvement in vascular repair has not been investigated and the underlying mechanisms remain to be fully elucidated. METHODS AND RESULTS: A rapidly progressive form of glomerulonephritis in wild type and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor, was studied. Calpastatin transgene expression prevented the repair of peritubular capillaries and the recovery of renal function, limiting mouse survival. In vitro analysis detected a significant reduction of both intracellular and extracellular calpain activities in transgene expressing cells, whereas Western blotting revealed that proangiogenic factors vascular endothelial growth factor and norepinephrine increased calpain exteriorization. In vitro, extracellular calpains increased endothelial cell proliferation, migration and capillary tube formation. In vivo, delivery of nonpermeable extracellular calpastatin was sufficient to blunt angiogenesis and vascular repair. Endothelial cell response to extracellular calpains was associated with fibronectin cleavage, generating fibronectin fragments with proangiogenic capacity. In vivo, fibronectin cleavage was limited in the kidney of calpastatin transgenic mice with nephritis. CONCLUSIONS: This study demonstrates that externalized calpains participate in angiogenesis and vascular repair, partly by promoting fibronectin cleavage and thereby amplifying vascular endothelial growth factor efficiency. Thus, manipulation of calpain externalization may have therapeutic implications to control angiogenesis.

The role of calpains in myocardial remodelling and heart failure.

Calpains are cytosolic calcium-activated cysteine proteases. Recently, they have been proposed to influence signal transduction processes leading to myocardial remodelling and heart failure. In this review, we will first describe some of these molecular mechanisms. Calpains may contribute to myocardial hypertrophy and inflammation, mainly through the activation of transcription factors such as NF-κB. They play an important role in the fibrosis process partly by activating transforming growth factor ß. They are also implicated in cell death as they cause the breakdown of sarcolemma and sarcomeres. Nevertheless, a key to understanding the molecular basis of calpain-mediated myocardial remodelling likely lies in the identification of mechanisms involved in calpain secretion, since cytosolic and extracellular proteases would have different functions. Finally, we will provide an overview of the available evidence that calpains are indeed actively involved in the common causes of heart failure, including hypertension, diabetes, atherosclerosis, ischaemia-reperfusion, atrial fibrillation, congestive failure, and mechanical unloading.

Prediction of high-degree steroid dependency in pediatric idiopathic nephrotic syndrome.

Most patients with idiopathic nephrotic syndrome are steroid-responsive, but about 50% relapse and often become steroid-dependent and exposed to long-term steroid complications. The aim of this study was to determine predictive risk factors for steroid and/or cyclosporine A (CyA) dependence. In France, steroid responsiveness is defined as remission after 1 month of oral prednisone (60 mg/m(2) per day) and-in the case of persistent proteinuria on day 30-three methylprednisolone pulses (MPP; 1 g/1.73 m(2) on days 1, 3, and 5). Thirty-five steroid-responsive children, followed between 1999 and 2006, were included in this study. Median age at diagnosis was 4.9 years. All patients initially received prednisone 60 mg/m(2) per day. Twenty-four of the 35 patients were steroid-dependent, with 12 requiring MPP. Of the latter 12 patients, 83.3% were treated with CyA during follow-up; in comparison, only 16.7% of the patients who did not receive MPP required CyA during follow-up (chi-square test, P = 0.001). T risk for steroid dependence was 100% in our cohort if remission was achieved after day 20. Patients who need MPP are at high risk to require CyA to achieve disease control. By identifying these children, we could use adequate immunosuppressive drugs earlier and reduce morbidity related to steroids and multiple relapses.