Sulfate homeostasis, NaSi-1 cotransporter, and SAT-1 exchanger expression in chronic renal failure in rats

It is known that hypersulfatemia, like hyperphosphatemia, occurs in chronic renal failure (CRF). The aim of this study was to assess the effects of CRF on sulfate homeostasis and on sodium sulfate cotransport (NaSi-1) and sulfate/oxalate-bicarbonate exchanger (Sat-1) expression in the kidney. In addition, sulfate homeostasis was compared with phosphate homeostasis.

Experimental studies were performed in adult male rats at three and six weeks after 80% subtotal nephrectomy (Nx) or sham-operation (S) (N = 9 per group). Transporter protein and mRNA expressions were measured by Western blot and RNase protection assay (RPA), respectively. Results were quantitated by densitometric scanning (Western) and electronic autoradiography (RPA), and were expressed in densitometric units (DUs; Western) and cpm (RPA).

Creatinine clearance was lower in Nx-3 compared with S-3 rats (0.23 vs. 0.51 mL/min/100 g body weight, P < 0.001) and was further impaired in Nx-6 rats (0.15 vs. 0.48, P < 0.001). Sulfatemia was significantly higher in Nx-3 rats (1.08 vs. 0.84 mmol/L, P < 0.05) and further increased in Nx-6 rats (1.42 vs. 0.90 mmol/L, P < 0.01). Fractional sulfate excretion (FESO4) was increased by twofold in Nx-3 and Nx-6 rats compared with corresponding S rats. Phosphatemia did not differ between Nx-3 rats and controls, but was increased in Nx-6 rats (P < 0.01). Total amounts of both NaSi-1 and Sat-1 proteins were significantly decreased in both Nx-3 and Nx-6 rats when compared with controls. However, NaSi-1 protein and mRNA densities did not significantly change in Nx-3 rats, but were significantly increased in Nx-6 rats when compared with controls (4.8 vs. 3.7 DU/microg protein, P < 0.05, and 7.1 vs. 2.8 cpm/microg RNA, P < 0.01, respectively, for protein and mRNA). In contrast to NaSi-1, Sat-1 protein density was significantly decreased both in Nx-3 (2.9 vs. 3.6 DU/microg protein, P < 0.05) and Nx-6 rats (2.4 vs. 3.4 DU/microg protein, P < 0.05), and Sat-1 mRNA density significantly decreased in Nx-6 rats (10.7 vs. 14.7 cpm/microg RNA, P < 0.05). Na-PO4 cotransporter (NaPi-2) protein total abundance and density were decreased at three and six weeks in Nx rats.

These results demonstrate that both NaSi-1 and Sat-1 total protein abundances are decreased in CRF, which may contribute to the increase in fractional sulfate excretion. Strikingly, NaSi-1 density was not decreased in CRF three weeks after Nx, and furthermore, increased six weeks after Nx, in contrast to NaPi-2 density, which was decreased at both times. The significance of this difference remains to be determined, but may explain why hypersulfatemia occurs earlier than hyperphosphatemia in CRF.