Abstract P127: Chromogranin A Pathway: From Pathogenic Molecule to Renal Disease

Abstract

Introduction: Chromogranin A (CHGA) is released into circulation with catecholamine from secretory granules of chromaffin cells and post-ganglionic sympathetic neurons. Several CHGA gene polymorphisms contributing to traits of autonomic blood pressure control, hypertension and hypertensive nephropathy have been identified. Plasma CHGA is elevated in hypertension and renal failure. This study seeks to understand the role of CHGA in the progression of CKD/ ESRD. Hypothesis: Kidney injury results in elevated expression of CHGA which in turn affects biochemical and physiological traits that determine progression and development of CKD/ESRD. Methods: The remnant kidney model was used to investigate the influence of CHGA on kidney function in response to injury. Distinction in response to kidney injury in wild-type (WT) and Chga-/- (KO) mice was evaluated by measuring glomerular function, fibrosis and microarray analysis. Mesangial cells were treated with CHGA to delineate pathway leading to inflammation and fibrosis. Results: Nephrectomy (Npx) exacerbated azotemia in WT mice compared to their KO counterparts. WT-Npx mice displayed far excess fibrosis as equated with KO-Npx. Gene expression profiling revealed greater mitochondrial dysfunction due to Npx in WT mice. Mesangial cells in culture treated with CHGA, triggered NO release, by a signaling mechanism involving SR-A. CHGA treatment augmented NO production by a 2-step mechanism involving upregulation of iNOS and the arginine transporter Slc7a7. CHGA-treated vs. untreated cells exhibited differential involvement of cytokine, chemokine, complement, acute phase pro-inflammatory markers and apoptotic pathway genes. Plasma creatinine and CHGA was measured in a twin population (N=740) and an inverse correlation between GFR and CHGA was observed. Therefore, in both mice and humans an inverse correlation suggested decrease in glomerular function with increasing plasma CHGA concentration. Conclusions: Kidney injury leads to elevated levels of CHGA which serves as an insult to the mesangial cells resulting in reduction of mitochondrial efficiency, concerted transcription of genes involved in NO production, inflammation and fibrosis, progression of CKD and development of ESRD.