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Discovery of vitamin D hormone as a negative regulator of the renin-angiotensin system.

Featured Article: Li YC, Kong J, Wei M, ChenZ-F, Liu SQ, Cao L-P. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-38. (2)

It is now well accepted that the vitamin D hormone is a pleotropic hormone that regulates a wide spectrum of biological processes beyond calcium and skeletal homeostasis. The establishment of this concept is in large part attributed to studies of genetic animal models with gene inactivation in the vitamin D endocrine system (1). As one of the scientists who first created the vitamin D receptor (VDR) knockout model, I have witnessed the rapid advance of this research field in the last 2 decades. One of my major contributions to this field was the discovery of the vitamin D hormone as a negative regulator of the renin-angiotensin system. This discovery has broad implications in the relationship between vitamin D and the renal and cardiovascular systems.

In 1998 I was recruited to the University of Chicago as an assistant professor in the Department of Medicine after completing my postdoctoral training in Marie Demay's laboratory at Massachusetts General Hospital, Harvard Medical School. In Demay's laboratory, I generated a genetic mouse line that carried a targeted deletion in the vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene (2). The mutant mice developed hypocalcemia, secondary hyperparathyroidism, and rickets, as expected, but they also had other abnormalities that were unknown at that time. Maria Demay was kind enough to allow me to bring the mice to Chicago to continue the study. It was very clear to me that as a junior faculty member I needed to develop new research projects.

Louis Pasteur once said, "In the fields of observation, chance favors only those minds which are prepared" (3). This is particularly true in this case. As I had long suspected that VDR knockout mice had unidentified phenotypes, I kept a close eye on subtle changes in this new genetic model. In the summer of 1999, when my postdoc brought some mice to the laboratory for tissue harvest, I noticed that the bedding of VDR knockout mice was very wet, suggesting they urinated a lot more than their wild-type counterparts. Puzzled and struck by this interesting observation, I took a few guesses and decided to look at renin expression in the kidney, simply because of the prominent role of the renin-angiotensin system in the regulation of the fluid and salt balance. When the Northern blot results came out, we were astonished to see that, without exception, all the VDR knockout mice showed increased renin expression that was several-fold higher than that of wild-type mice, indicating that VDR signaling negatively regulated renin expression. This observation was reported in our 2002 article featured here. Indeed, further investigations revealed that VDR knockout mice developed hyperreninemia, hypertension, cardiac hypertrophy, and polyuria, and these abnormalities were independent of vitamin D's actions on calcium and skeletal homeostasis. Our subsequent studies demonstrated that the vitamin D hormone downregulates renin gene expression by targeting the cAMP-PKA-CREB (cAMP-protein kinase A-cAMP-responsive element binding protein) signaling pathway that promotes renin transcription (4).

The finding that the vitamin D hormone inhibits the renin-angiotensin system generated much excitement in the field. I was invited to present our work at media briefings and a plenary session at the American Society for Bone and Mineral Research annual meeting in 2002. Our work was also cited in an article about vitamin D in the Chicago Tribune. Following our publication, vitamin D suppression of renin was confirmed in patients with chronic kidney disease. Consistently, epidemiological studies confirmed an inverse correlation between vitamin D status and plasma renin and angiotensin II concentrations in several patient populations. This discovery served as a molecular basis to explain the link between vitamin D deficiency and renal and cardiovascular diseases that was widely reported in the literature. It stimulated research interest in the field and inspired more studies to investigate the renal and cardiovascular actions of the vitamin D hormone and its noncalcemic analogs in both preclinical and clinical settings. Many clinical trials were designed on the basis of the principle established in this work. It is indeed gratifying to see that this report, with a seminal observation, has been so highly cited since its publication.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: The research described in this report was supported by NIH grants R01 HL085793 and K01 DK59327.

Expert Testimony: None declared.

Patents: None declared.

References

(1.) Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 2008;29:726-76.

(2.) Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 1997;94:9831-5.

(3.) Peterson H, ed. A treasury of the world's great speeches, each speech prefaced with its dramatic and biographical setting and placed in its full historical perspective. New York: Simon and Schuster; [1954]. p 473.

(4.) Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, et al. 1,25-Dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007;282:29821-30.

Yan Chun Li [1] *

[1] Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL.

* Address correspondence to the author at: Department of Medicine, The University of Chicago, 900 E. 57th Street, KCBD 9110, Chicago, IL 60637. Fax 773-702-2281; e-mail: cyan@medicine.bsd.uchicago.edu.

Received November 19, 2013; accepted November 26, 2013.

Previously published online at DOI: 10.1373/clinchem.2013.216150

[2] This article has been cited more than 670 times since publication.
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Title Annotation:Citation Classic
Author:Li, Yan Chun
Publication:Clinical Chemistry
Geographic Code:1USA
Date:Mar 1, 2014
Words:1063
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