Renin-Angiotensin System Regulates Il-1β Induced Androgen Receptor/Collagen Cascade in the Pathogenesis of Dihydropyridine Induced Gingival Overgrowth

Dihydropyridine calcium channel blockers are frequently used in therapy of hypertension. Among
many side effects, Dihydropyridine has been found associated with gingival overgrowth that usually
occurs within one third of the patients. Nifedipine, the first generation of dihydropyridine, causes the
gingival overgrowth through androgen receptor (AR)/collagen cascade in dihydropyridine induced
gingival overgrowth (DIGO) patients. The rennin-angiotensin system is a hormone system that also
regulates blood pressure and fluid balance. We propose that angiotensin II (Ang II) is an intermediate
inducer to cause the gingival overgrowth in hypertension patients. The aim of this project is to verify the
mechanism of Ang II regulates AR/collagen axis through angiotensin II type I receptor (AT1R) in
DIGO. Our further study will evaluate the therapeutic efficiency of angiotensin-converting enzyme
(ACE) inhibitor and AT1R antagonists for DIGO cell. There are four specific aims will be addressed
here: Year 1: Aim 1: To clarify the mechanism of RAS on AR regulation in gingival fibroblast under
the stimulation of IL-1β and/or nifedipine; Aim 2: To verify the inter-relationship of TGF-β1 and AR in
RAS/AT1R/AR axis as DIGO cells are stimulated by IL-1β and/or nifedipine. Year 2: Aim 1: To further
verify the RAS/AT1R/TGFβ1/AR/collagen axis in DIGO fibroblast; Aim 2: To characterize the
mechanism that ACE inhibitors and AT1R antagonists inhibit collagen expression by decreasing
RAS/AT1R/TGFβ1/AR activity. We expect ACE inhibitors and AT1R antagonists act as a potential
therapeutic drug for the prevention and treatment of DIGO by suppressing AR activity, and
subsequently reducing collagen over production. In the near future, the results of this study can imply
that ACE inhibitors and AT1R antagonists are promising potential chemopreventive and
chemotherapeutic agents for DIGO.