Tubular handling and regulation of sulphate.

Sulphate, the fourth most abundant anion in human several considerations raise the possibility that certain plasma, is known to play an essential role in a variety of the skeletal abnormalities seen in vitamin D of biochemical processes [1]. The importance of deficiency could result from abnormal sulphate metasulphate has been demonstrated recently by the identibolism. First, a number of the pathological features fication of mutations in a sulphate transport protein seen in 1,25(OH)2D deficiency states are not easily (diastrophic dysplasia sulphate transporter; DTDST) explained solely by changes in calcium and phosphate in three different types of osteochondrodysplasia, diasmetabolism. Thus, although hypocalcaemia and hypotrophic dysplasia, type IB achodrongenesis and type II phosphataemia easily account for the impairment in atelosteogenesis [2–4]. In these osteochondrodysplasmineral deposition typical of rickets and osteomalacia ias, undersulphation of cartilage proteoglycans is asso[13], the disorganization of the chondrocyte columns ciated with abnormalities affecting the organization of seen in rachitic cartilage and the presence of abnorcollagen fibrils, the tinctorial properties of proteomalities in the maturation of chondrocytes [13,14] glycans and the number and morphology of chondroare more difficult to attribute to this mechanism. cytes. The severity of the phenotype appears to be Furthermore, changes in the physical properties of correlated with the predicted effect of the mutations proteoglycan aggregates in rachitic rat bone [15], and on the residual activity of the DTDST protein [4]. a reduction in sulphate fixation in the matrix of growth Despite their potential importance, sulphate levels are plate cartilage in vitamin D-deficient rats have also almost never measured in clinical practice, and little is been reported [16 ], findings that are consistent with known about the factors that regulate sulphate the presence of abnormalities of sulphate metabolism homeostasis in mammals. in 1,25(OH)2D deficiency. Finally, the intestine and The kidney plays a crucial role in maintaining kidney, two of the principal target organs for sulphate homeostasis. Sulphate is filtered freely at the 1,25(OH)2D action, are also known to represent the glomerulus and reabsorbed in the proximal tubule. two most important tissues implicated in the regulation Only 5–20% of the filtered load is excreted in urine. of extracellular concentrations of inorganic sulphate Tubular sulphate uptake from lumen to blood depends [5]. Nevertheless, no direct evidence for abnormalities on the activity of a sodium-coupled sulphate transport in the circulating levels of sulphate in vitamin (co-transport at the luminal membrane) [5]. Once D-deficient animals has been reported. sulphate has been accumulated within the tubular To explore the possibility that vitamin D status epithelial cell, its exit across the peritubular face of the regulates sulphate homeostasis, plasma sulphate levels, cell is mediated by anion exchange. Recently, two renal sulphate excretion and the expression of the renal sulphate transporters, a NaSi-1 co-transporter and a NaSi-1 and Sat-1 sulphate transporters were evaluated sulphate/oxalate–bicarbonate anion exchanger (Sat-1) in vitamin D-deficient (D−D−) rats and in D−D− rats have been identified [6–8] and implicated in this rendered normocalcaemic by either vitamin D or calphysiological process. The NaSi-1 co-transporter and cium/lactose supplementation [17]. D−D− rats had Sat-1 protein have been localized to the apical and significantly lower plasma sulphate levels than control basolateral membrane of the proximal tubule, respectanimals (0.93±0.01 and 1.15±0.05 mM, respectively, ively [9–11]. In addition to the proximal tubule, NaSi-1 P<0.05), and fractional sulphate renal excretion was co-transporter is expressed in the ileum [12], while ~3-fold higher comparing D−D− and control rats. A Sat-1 is also expressed in the liver [7]. These two decrease in renal cortical brush border membrane transporters are thought to be responsible for inorganic (BBM) NaSi-1 co-transport activity, associated with a sulphate entry into and exit from the proximal parallel decrease in both renal NaSi-1 co-transport tubular cells. protein and mRNA content (78±3% and 73±3% We have been interested in the possibility that vitdecreases, respectively, compared with control values), amin D status regulates sulphate metabolism. Indeed, was also observed in D−D− rats. The expression of Sat-1 (mRNA and protein) in the kidney and in the Correspondence and offprint requests to: Caroline Silve, INSERM U426, Faculté de Médecine Xavier Bichat, Paris, France. liver, and of NaSi-1 (mRNA) in the ileum were not