Calcium-sensing in the kidney: the calcium-sensing receptor and beyond – Kid-Ca-Sens

Renal tubular calcium handling is a major determinant of urinary calcium excretion and plasma calcium concentration. This process is tightly regulated by a number of factors, including the extracellular calcium concentration itself via its action on the calcium-sensing receptor CaSR expressed in the renal tubule. Recently, we have shown that CaSR is only significantly expressed in the thick ascending limb of the loop of Henle (both medullary and cortical) where it inhibits calcium absorption by decreasing the paracellular pathway permeability to calcium. This, obviously, challenged the preexisting concepts. In addition, we showed that activating CaSR does not change sodium, water and acid excretions whereas increasing extracellular Ca concentration does, suggesting that Ca-sensing mechanisms distinct from CaSR do exist in the kidney; preliminary data suggest that GPRC6A, a close relative to CaSR, can be one of those Ca-sensing mechanisms. To further increase our understanding of these phenomena, we aim i) at deciphering the molecular targets of CaSR in the renal tubule, ii) at unraveling the mechanisms of CaSR-independent Ca-sensing along the renal tubule. The first objective will be addressed by assessing the tubular phenotype of claudin-16 and claudin-19 KO mice, their ability to respond to CaSR agonists/antagonists, and the CaSR-dependent changes in trafficking of these proteins and gene expression. The second objective will require the development of highly specific GPRC6A or CaSR agonists and antagonists and the assessment of GPRC6A function in the distal nephron by mixed genetic and pharmacologic approaches.
Our approach integrates specific and complementary areas of investigation, including, in vivo animal phenotyping, in vitro microperfusion, cellular and molecular biology, new drugs designing and development.
Our project is ideally positioned to make research breakthroughs in the area of calcium-sensing in the kidney and should provide valuable information regarding the pathophysiology and treatment of Cldn-associated diseases, as well as on the role of the GPRC6A