The proton-activated ovarian cancer G protein-coupled receptor 1 (OGR1) is responsible for renal calcium loss during acidosis

Abstract

Hypercalciuria is a common feature during metabolic acidosis and associates to nephrolithiasis and nephrocalcinosis. The mechanisms sensing acidosis and inducing increased urinary calcium excretion are still unknown. Here we tested whether mice deficient for proton-activated Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) have reduced urinary excretion of calcium during chronic metabolic acidosis. In the kidney, OGR1 mRNA was found in cells of the glomerulus, proximal tubule, and interstitium including endothelial cells. Wild type (OGR1+/+) and OGR1 knockout (OGR1−/−) mice were given standard chow without (control) or loaded with ammonium chloride for one or seven days to induce acute or chronic metabolic acidosis, respectively. No differences in responding to the acid load were observed in the knockout mice, except for higher plasma bicarbonate after one day. Bone mineral density, resorption activity of osteoclasts, and urinary deoxypyridinoline were similar between genotypes. During metabolic acidosis the expression levels of key proteins involved in calcium reabsorption, i.e. the sodium/proton exchanger (NHE3), the epithelial calcium-selective channel TRPV5, and the vitamin Ddependent calcium binding protein calbindin-D28k were all higher in the knockout mice compared to wild type mice. This is consistent with the previous demonstration that OGR1 reduces NHE3 activity and its surface expression in HEK293 cells. Wild-type mice displayed a non-linear positive association between urinary proton and calcium excretion which was lost in the knockout mice. Thus, OGR1 is a pH sensor involved in the hypercalciuria of metabolic acidosis by controlling NHE3 activity in the proximal tubule. Hence, novel drugs modulating OGR1 activity may improve renal calcium handling.

Differential Roles of Extracellular Histidine Residues of GPR68 for Proton-Sensing and Allosteric Modulation by Divalent Metal Ions

“…GPR68 is an understudied orphan G-protein coupled receptor (oGPCR). First cloned from an ovarian cancer cell line for ovarian cancer G-protein-couple receptor 1 (therefore also known as OGR1 in the literature), it is widely expressed in most tissues and cells − and functions as a proton-sensing receptor. , Together with two other orphan receptors, GPR4 and GPR65 (previously known as TDAG8), they form a subfamily of proton-sensing GPCRs. − In responding to acidic extracellular conditions, GPR68 couples to multiple downstream signaling pathways via different families of G-proteins in different cells, including G q/11 , G s , G i/o , and G 12/13 , ,,, and has been implicated in a range of biological processes and pathological conditions, including pH homeostasis, insulin secretion, bone metabolism, learning and memory, blood flow and mechanosensing, inflammation, tumor metastasis and growth, and hematopoiesis. ,− As one of the understudied GPCR targets of the NIH funded Illuminating the Druggable Genome (IDG) program (), GPR68 has been receiving increasing attention in recent years and represents a potential therapeutic target for drug design and development.…”

The Molecular Effects of Dietary Acid Load on Metabolic Disease (The Cellular PasaDoble: The Fast-Paced Dance of pH Regulation)

“…Urinary analysis of patients with metabolic syndromes reflects metabolic or extracellular acidosis-activated calcium mobilization through increased renal excretion of calcium (Carnauba et al, 2017). This pathway is further evidenced by the requirement of OGR1 (a GPCR), in metabolic acidosis-induced calcium excretion into urine by kidney cells (hypercalciuria) (Abbasalizad Farhangi et al, 2019;Dimke, 2020;Imenez Silva et al, 2020).…”

Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis

“…Pumroy R.A. contends that the normal function of TRPV5/6 is closely related to OP and kidney calculi [ 168 ]. Recent studies on the pH microenvironment of bone tissue and TRPV5 reveal that the occurrence of metabolic acidosis reduces the expression and function of TRPV5 and the absorption of Ca 2+ at least at the mRNA level [ 132 , 169 ]. There are numerous types of hormones that can elicit changes in the level of TRPV5.…”