David Gardner, MD
Our laboratory is interested in the hormonal regulation of cardiovascular and renal function. More specifically, we have focused our attention on the cardiac natriuretic peptides and their receptors, and the liganded vitamin D receptor system for investigation.
While it is generally accepted that vitamin D plays an important role in the regulation of mineral (i.e. calcium and phosphorous) homeostasis and normal bone growth, there is a growing body of evidence suggesting that it also plays a palliative role in protecting the cardiovascular system from the effects of adverse stimuli. For example, it suppresses plasma renin levels and reduces blood pressure in the mouse and in humans, and it reverses cardiac hypertrophy seen in patients with end stage renal disease on dialysis. We have shown previously that vitamin D reverses various components of the hypertrophic phenotype in cultured cardiac myocytes, and that mice lacking the vitamin D receptor have significant cardiac hypertrophy, albeit in the presence of moderate hypertension. We have recently constructed a mouse which has a selective deletion of the vitamin D receptor gene in the heart. These mice have cardiac hypertrophy without evidence of fibrosis implying that the liganded vitamin D receptor has direct effects at the level of the cardiac myocyte.
Receptors for the NPs can be divided into two major classes. The first, which includes natriuretic peptide receptors (NPR) A and B, possesses particulate guanylyl cyclase activity. These receptors are believed to mediate most of the biologically important effects of the natriuretic peptides, with ANP and BNP binding to NPR-A and CNP associating largely with NPR-B. The second category includes NPR-C, a single transmembrane domain receptor with a truncated intracellular domain. This receptor seems to operate in a clearance mode in vivo, although there is growing evidence that it also possesses signaling activity. We are attempting to understand the regulation of the type A receptor in heart, where it appears to play an important role in controlling interstitial fibrosis, and in the kidney, where it is significantly upregulated by increases in medullary tonicity through a mechanism involving the serum and glucocorticoid inducible kinase (sgk). We are also exploring the unique properties of the B type receptor by selectively deleting it in individual cell types using a Cre-lox approach. Using this approach we hope to explore the role of NPR-B in controlling bone growth, cardiac hypertrophy and reproductive function in the mouse model.
Collectively, these studies should provide us with better definition of the mechanisms whereby these various hormones exert their largely protective effects in the heart, blood vessels and kidneys, and, inferentially, identify potential targets for therapeutic intervention.