Postdoctoral Research Associate University of Georgia Athens, Georgia, United States
Background: The hormone relaxin, which is usually associated with pregnancy, has been shown to play an important role in the regulation of the cardiorenal system. Recombinant fusion protein relaxin may have potential as a treatment for chronic kidney disease and chronic heart failure, but its mechanistic effects on kidney hemodynamics and fluid status remain incompletely understood. Much of our understanding of relaxin pharmacology comes from the studies of rats. Methods: The objectives of this study were to 1) couple a QSP model of cardiorenal function with experimental observations of acute renal hemodynamics and natriuretic responses to relaxin in rats in order to determine mechanistic effects of relaxin required to explain the experimental data, and 2) to predict chronic effects of relaxin on clinically important but difficult-to-measure variables such as glomerular capillary hydrostatic pressure (Pgc) and fluid status. Results: By fitting the model to experimental data, we determined that, as expected, relaxin’s established strong vasodilatory effects on afferent/efferent renal arterioles can explain observed increases in renal blood flow (RBF) and Na+ excretion. However, these mechanisms could not fully explain the experimental data (i.e. changes in glomerular filtration rate (GFR), Pgc, and Na+ excretion rate). Two additional relaxin mechanisms were necessary: an increase in glomerular ultrafiltration coefficient Kf (i.e. glomerular filtration surface area, max increase 150%) and a decrease in plasma [Na+] setpoint for vasopressin secretion (max decrease: -4 mEq/L). After fitting to two acute studies ( < 3 hours), the model was able to predict the response to changes in RBF (3 hours) and plasma osmolality (4 days) in a third study in rats. Conclusion: Simulations of chronic treatment with relaxin predict that relaxin produces sustained reductions in Pgc, supporting its potential for renoprotection.
