Anti-EDN1 monoclonal antibody, clone 4C9D0

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-beta activation in podocytes; however, it is not clear how TGF-beta signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-beta signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

Sarcoidosis is a chronic inflammatory disease, characterized by granulomatous inflammation, prominently involving the respiratory system. The etiology of this disease has not yet been elucidated and the contribution of genetic is not yet completely understood. We searched for novel candidate genes, utilizing a system biology approach, based on data from published transcriptional, proteomic and linkage studies of sarcoidosis. The search revealed several new potential candidate genes involved in the pathogenesis of inflammatory lung diseases: 25-(OH)-vitamin D-3-1 alpha-hydroxylase (CYP27B1), endothelin-1 (EDN1) and glutathione S-transferase Pi (GSTP1). Variants of selected polymorphisms: -1260/C>A in CYP27B1, Lys198Asn in EDN1, and Ile105Val in GSTP1, were examined to determine if they confer susceptibility to sarcoidosis, based on an analysis of 180 Slovenian patients in comparison with 283 healthy controls. Polymerase chain reactions using allele-specific oligonucleotides were performed. This disease was not significantly associated with genotypes CC at -1260/C>A polymorphism in CYP27B1 (P = 0.68, odds ratio (OR) = 1.10, 95% confidence interval (CI) = 0.75-1.61), GG genotype at Lys198Asn polymorphism in EDN1 (P = 1.00, OR = 0.97, 95% CI = 0.65-1.44) and AA genotypes at Ile105Val polymorphism in GSTP1 (P = 0.53, OR = 0.87, 95% CI = 0.60-1.27). There was no association of polymorphisms in any of the genes with sarcoidosis.