Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na⁺-dependent phosphate absorption and expression of the Na⁺-P_i cotransporter NaPi-IIb in small intestine

Abstract

During metabolic acidosis, P i serves as an important buffer to remove protons from the body. Pi is released from bone together with carbonate buffering protons in blood. In addition, in the kidney, the fractional excretion of phosphate is increased allowing for the excretion of more acid equivalents in urine. The role of intestinal P i absorption in providing Pi to buffer protons and compensating for loss from bone during metabolic acidosis has not been clarified yet. Inducing metabolic acidosis (NH 4Cl in drinking water) for 2 or 7 days in mice increased urinary fractional P i excretion twofold, whereas serum Pi levels were not altered. Na ϩ -dependent Pi transport in the small intestine, however, was stimulated from 1.89 Ϯ 3.22 to 40.72 Ϯ 11.98 pmol/mg protein (2 days of NH 4Cl) in brush-border membrane vesicles prepared from total small intestine. Similarly, the protein abundance of the Na ϩ -dependent phosphate cotransporter NaPi-IIb in the brush-border membrane was increased 5.3-fold, whereas mRNA levels remained stable. According to immunohistochemistry and real-time PCR NaPi-IIb expression was found to be mainly confined to the ileum in the small intestine, and this distribution was not altered during metabolic acidosis. These results suggest that the stimulation of intestinal P i absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone. phosphate SEVERAL MECHANISMS CONTRIBUTE to the buffering and elimination of excessive protons and acid equivalents during metabolic acidosis. Besides respiration, increased release of buffer substances from bone and stimulated reabsorption of bicarbonate and increased excretion of protons by the kidneys are the major mechanisms to restore acid-base balance (11, 16). Excretion of protons by the kidney requires so called titratable acids, i.e., ammonia, citrate, and phosphate, buffering protons in urine in the collecting duct and thus increasing the maximal acid excretion rate (16). The renal excretion of ammonia and phosphate is highly increased during metabolic acidosis, whereas excretion of citrate is decreased (3). Ammonia (NH 3 ) is synthetized from glutamine metabolism in the kidney proximal tubule in response to metabolic acidosis (27). In addition, it is thought that inhibition of renal reabsorption of phosphate contributes mainly to increased phosphate excretion (1). In a rat model for metabolic acidosis, a decrease in mRNA and protein of the major Na ϩ -P i cotransporter NaPi-IIa as well as in Na ϩ -dependent P i uptake into brush border membrane (BBM) vesicles (BBMV) has been found (1). Systemic P i levels are only slightly decreased during metabolic acidosis, an effect that has been attributed to the acid-stimulated release of P i from bone together with Ca 2ϩ and carbonate (23). Indeed, the release of phosphate from bone during short-and long-term metabolic acidosis in in vivo and in in vitro models has been extensively documented a...

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats

“…The present finding of hyperphosphaturia in CMA rats is consistent with prior reports in human (16) and mouse mineral acidosis (24). However, the finding that intestinal P i uptake into small intestinal apical vesicles is increased in parallel with increased small intestinal NaPiIIb transporter protein in mice with CMA suggests that intestinal P i hyperabsorption may play a major role in the hyperphosphaturia of acidosis.…”

“…Cancellous microarchitecture was analyzed in vivo at the same skeletal location using CT (Viva CT40; Scanco Medical, Bassersdorf, Switzerland) (19,24). The scans were performed with the following instrument settings: 55 kV, 145 A, 300-ms integration time, 2,000 projections on 360°, 2048 charge-coupled device detector array, cone-beam reconstruction.…”

Acid-Base Status Determines the Renal Expression of Ca2+ and Mg2+ Transport Proteins

“…Mice that receive NH 4 Cl develop chronic metabolic acidosis that is characterized by a slight decrease in blood pH, a reduced serum HCO 3 Ϫ concentration, and, importantly, a low urine pH as substantiated in this study (24). Vennekens et al (31) recently demonstrated that extracellular protons inhibit TRPV5 in vitro by titrating glutamate 522 in the extracellular loop between the fifth putative transmembrane domain and the pore region as shown by Yeh et al (32).…”

Phosphate transporters: a tale of two solute carrier families

“…NaPi-IIa is expressed in osteoclasts (37,53) and chondrocytes (62), whereas osteoblasts express both NaPi-IIa and NaPi-IIb (59). NaPi-IIb is responsible for transcellular P i absorption in the small intestine and is regulated by dietary P i (80) and metabolic acidosis (91). In the liver, NaPi-IIb is involved in the reabsorption of P i from primary hepatic bile (35).…”