Tubule urate and PAH transport: sensitivity and specificity of serum protein inhibition.

Abstract

Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [14C]urate and p-[3H]aminohippurate ([3H]PA) in rabbit S2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, we examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and gamma-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation of urate and PAH by isolated nonperfused segments [50% inhibition (K0.5) = 0.4 and 0.65 g/dl, respectively]. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit gamma-globulin, but not by Cohn-fractionated bovine serum albumin. alpha-Lactalbumin and beta-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and gamma-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and gamma-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S2 proximal tubules. We suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH.