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

Yuqing Chen^*,, Manjula Mahata^*, Fangwen Rao^*, Srikrishna Khandrika^*, Maite Courel^*, Maple M. Fung^*, Kuixing Zhang^*, Mats Stridsberg, Michael G. Ziegler^*, Bruce A. Hamilton^*, Michael S. Lipkowitz, Laurent Taupenot^*, Caroline Nievergelt^*, Sushil K. Mahata^|| and Daniel T. O'Connor^||,¶,**

Departments of ^* Medicine and ^¶ Pharmacology and ^** Center for Human Genetics and Genomics, University of California at San Diego, La Jolla, California; ^|| Veterans Affairs San Diego Healthcare System, La Jolla, California; Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Medicine, Mt. Sinai School of Medicine, New York, New York; and Renal Division, Peking University First Hospital, Beijing, China

Correspondence: Dr. Sushil K. Mahata or Dr. Daniel T. O'Connor, Department of Medicine, University of California at San Diego School of Medicine and Veterans Affairs San Diego Healthcare System, 9500 Gilman Drive, La Jolla, CA 92093-0838. Phone: (858) 534-0661; Fax: (858) 534-0626; E-mail: smahata{at}ucsd.edu or doconnor{at}ucsd.edu

Received for publication November 7, 2008. Accepted for publication February 16, 2009.

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-β1 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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673