Nitric Oxide Signaling and Urinary Stone Disease
The aim of this pilot project on nitric oxide signaling and urinary stone disease is to identify novel mechanisms that contribute to the initiation and progression of calcium deposits in ectopic tissues.
Our central hypothesis is that losses in nitric oxide (NO) signaling are major contributors to accelerated renal stone formation, and that reactivation of NO signaling will abrogate renal stone formation mice in vivo. This pilot project leverages ongoing National Institutes of Health-funded work in the laboratory of Mayo Clinic cardiovascular disease scientist Jordan D. Miller, Ph.D., including a clinical trial testing sGC activators in humans with calcific aortic valve disease.
The two specific aims of the pilot project are:
- To determine whether reactivation of NO signaling with HMR1766 will abrogate renal stone formation in hypercholesterolemic mice given L-NAME in drinking water
- To determine whether increasing NO signaling will abrogate renal calcium deposition in glyoxylate-induced nephrocalcinosis in mice
Redifferentiation of cells to an osteoblast-like phenotype is thought to be central to the progression of calcified lesions in cardiovascular tissues. The vast majority of risk factors for development of cardiovascular calcification (such as aging, hypercholesterolemia, hypertension and smoking) are associated with increases in oxidative stress, which is ubiquitously associated with reductions in nitric oxide signaling. Little is known, however, about the role of nitric oxide signaling in the pathogenesis of ectopic calcium deposition in other tissues.
Dr. Miller's lab recently conducted a study in which hypercholesterolemic mice were given L-NAME in drinking water for six months. The initial focus was on cardiovascular tissue, where we found that chronic treatment of mice with L-NAME resulted in profound increases in cardiovascular calcification and aortic valve dysfunction.
After confirming our primary hypothesis that reducing NO bioavailability would accelerate cardiovascular calcification, we next sought to determine whether reducing NO signaling would result in induction of ectopic calcification in other tissues where calcified nodule formation is common. Importantly, we found that reducing NO signaling resulted in dramatic increases in calcium deposition in mouse kidneys.
Thus, we believe we have identified a novel animal model of nephrocalcinosis in which to test therapeutic interventions aimed at slowing initiation and progression of renal stone formation.
We also discovered that reactivation of sGC using anthranilic acid derivatives (such as HMR1766) slows progression of cardiovascular calcification and aortic valve dysfunction in hypercholesterolemic mice. Little is known about the therapeutic efficacy of increasing nitric oxide bioavailability in the context of renal stone formation.