Our interest lies in developing mathematical models to investigate transport mechanisms in the kidney, at different levels (cell, tubule, organ). Our recent work focuses on (a) the regulation of calcium reabsorption along the different nephron segments; (b) the mechanisms by which the cortical collecting duct alternatively mediates the reabsorption or secretion of NaCl; (c) the interactions between nitric oxide, superoxide, and oxygen, and their effects on NaCl reabsorption in the renal medulla.
Simplified representation of intracellular calcium signaling in vascular smooth cells. Plasma membrane Ca2+ pumps (PMCA) and Na+/Ca2+ exchangers (NCX) mediate Ca2+ efflux, whereas voltage-operated Ca2+ channels (VOCa) carry Ca2+ in when activated by membrane depolarization. Calcium stores in the sarcoplasmic reticulum (SR) are filled up by SR Ca2+ pumps (SERCA), and release Ca2+ into the cytosol via receptors that are sensitive to ryanodine (RyR) or inositol 1,4,5-trisphosphate (IP3R). Agonist binding to G protein-coupled receptor leads to the formation of IP3, thereby activating receptor-mediated Ca2+ release and triggering a signaling cascade. We developed a model of Ca2+ signaling in descending vasa recta (DVR) pericytes to elucidate the mechanisms by which angiotensin II generates cytosolic Ca2+ oscillations in DVR, as well as the effects of nitric oxide on DVR contraction.
Schematic representation of rodent adrenal steroidogenesis.
We built a mathematical model of steroidogenesis in rodents to predict the effects of different diets on the production of aldosterone and corticosterone, as well as the intermediate metabolites. The model predicted that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was subsequently confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates the renal retention of potassium by stimulating the colonic H+,K+-ATPase in the kidney.
Feedback mechanisms involving nitric oxide (NO), superoxide (O2-) and oxygen (O2). Our studies aimed to elucidate the effects of NO and O2- on vascular and tubular functions in the renal outer medulla. NO synthesis is O2-dependent, but red blood cell (RBC) trapping of NO may also decrease under hypoxic conditions, via uncertain mechanisms. NO is scavenged rapidly by hemoglobin (Hb), and to a smaller extent by O2-. The relationship between O2- synthesis and PO2 remains unclear. Superoxide dismutase (SOD) consumes O2- at a faster rate than NO does. As a vasodilator, NO enhances medullary perfusion and O2 supply, whereas O2- exerts opposite effects. NO inhibits NaCl reabsorption by the TAL and therefore O2 consumption, whereas O2- stimulates both. Not shown on the diagram are the many other paracrine agents that act on vascular contraction and tubular NaCl reabsorption.
Aurélie Edwards, DR2, CNRS
Luciana Morla, Engineer
David Granjon, Doctoral student
Edwards A, Castrop H, Laghmani K, Vallon V, Layton AT. Effects of NKCC2 isoform regulation on NaCl transport in thick ascending limb and macula densa: a modeling study. Am J Physiol Renal Physiol 307: F137-F146, 2014. PMID: 24848496.
Edwards A, Layton AT. Calcium dynamics underlying the afferent arteriole myogenic response. Am J Physiol Renal Physiol 306: F34-F48, 2014. PMID: 24173354.
Bonny O, Edwards A. Calcium reabsorption in the distal tubule: Regulation by sodium, pH, and flow. Am J Physiol Renal Physiol 304: F585-F600, 2013. PMID: 23152295.
Tournus M, Seguin N, Perthame B, Thomas SR, Edwards A. A model of calcium transport along the rat nephron. Am J Physiol Renal Physiol 305: F979-F994, 2013. PMID: 23761679.
Edwards A, Layton AT. Impact of nitric oxide-induced vasodilation on outer medullary NaCl transport and oxygenation. Am J Physiol Renal Physiol 303: F907-F917, 2012. PMID:22791340.
Elabida A*, Edwards A*, Salhi A, Azroyan A, Fodstad H, Meneton P, Doucet A, Bloch-Faure M, Crambert G. Chronic potassium depletion increases adrenal progesterone production which is necessary for efficient renal retention of potassium. Kidney International 80: 256-262, 2011. PMID: 21326170.
Azroyan A, Laghmani K, Crambert G, Mordasini D, Doucet A, Edwards A. Regulation of pendrin by pH: Dependence on glycosylation. Biochem J 434; 61-72, 2011. PMID: 21073444.
Edwards A. Modeling transport in the kidney: Investigating function and dysfunction. Am J Physiol Renal Physiol 298: F474-F484, 2010. PMID: 19889951.
Edwards A and Pallone TL. Mechanisms underlying Angiotensin II induced calcium oscillations. Am J Physiol Renal Physiol 295: F568-F584, 2008. PMID: 18562632.