Chromogranin A Regulates Renal Function by Triggering Weibel–Palade Body Exocytosis

Abstract

Chromogranin A (CHGA), a protein released from secretory granules of chromaffin cells and sympathetic nerves, triggers endothelin-1 release from endothelial cells. CHGA polymorphisms associate with an increased risk for ESRD, but whether altered CHGA-endothelium interactions may explain this association is unknown. Here, CHGA led to the release of endothelin-1 and Weibel-Palade body exocytosis in cultured human umbilical vein endothelial cells. In addition, CHGA triggered secretion of endothelin-1 from glomerular endothelial cells and TGF-␤1 from mesangial cells cocultured with glomerular endothelial cells. In humans, plasma CHGA correlated positively with endothelin-1 and negatively with GFR. GFR was highly heritable in twin pairs, and common promoter haplotypes of CHGA predicted GFR. In patients with progressive hypertensive renal disease, a CHGA haplotype predicted rate of GFR decline. In conclusion, these data suggest that CHGA acts through the glomerular endothelium to regulate renal function.

Glomerular Filtration

“…Elevations in circulating levels of other potential mediators of progressive renal damage have been reported; however, it is difficult to ascribe a cause and effect to such associations. In the study by Chen et al, 1 the authors propose that levels of CHGA-stimulated release of endothelin depend on genotype and are accurately mirrored by levels in the circulation; however, as with previous studies, it is difficult to ascribe a causative role in decreased GFR to either the level of circulating CHGA or endothelin. Thus, although individuals with ESRD have higher plasma levels of CHGA than those with CKD and both were higher than in normal individuals, it is unclear whether genetic variation affects plasma levels that mediate the decline in renal function or the impairment in renal function alters CHGA metabolism and/or excretion with consequent increases in plasma level.…”

“…One of the challenges presented by these studies is to define the mechanisms by which a given genetic variant affects a pathophysiologic disorder. This inevitable quandary confronts the study of Chen et al 1 in this issue of JASN. The authors previously reported that a genetic polymorphism of chromatogranin A (CHGA), a soluble protein released from secretory granules of chromaffin cells and sympathetic nerves, predicts hypertensive ESRD in black patients.…”

“…Using cultured human umbilical vein endothelial cells, Chen et al 1 now show that CHGA increases release of endothelin along with other peptides typically stored in WeibelPalade bodies, including von Willebrand factor and angiopoietin 2. CHGA also increases endothelin secretion from mouse glomerular endothelial cells, and co-culture of CHGA-exposed glomerular endothelial cells with mesangial cells potentiates secretion of TGF-␤1.…”

“…4,5 More recently, whole-genome scans of individuals with reduced renal function identified chromosomal "hotspots" that associate with decreased GFR (2p, 2q, and 7p), although precise identification of the relevant genes and understanding of their role in progressive damage are unknown. 6 -9 Chen et al 1 now provide evidence that those variations in the gene encoding CHGA also associate with decreased levels of GFR. These findings complement early functional studies showing that sympathetic tone can directly-and through stimulation of other substances including endothelin-constrict the afferent/efferent arterioles and glomerular capillary bed to decrease GFR and also activate profibrotic factors, including angiotensin, endothelin, and TGF-␤, promoting renal scarring.…”

“…The biomarker potential for endothelin suggested in the study by Chen et al 1 is complicated by its rapid clearance from the circulation (plasma half-life of 1 to 2 min). 13 In addition, secretion of endothelin is polarized, such that most of the endothelium-derived peptide goes toward the basolateral, not circulatory, direction.…”