Mechanisms of oedema in nephrotic syndrome: old theories and new ideas.

The intrarenal site of sodium retention was determined by an in vivo micropuncture study in the unilateral model of puromycin aminonucleoside (PAN)-induced proteinuria, which allows the study of a nephrotic and a normal control kidney within the same animal. Sodium delivery to the collecting duct was not different in the two kidneys while the urinary excretion of sodium was 3-fold lower in the nephrotic kidney compared with the control kidney, suggesting that stimulation of tubular sodium reabsorption originated in the collecting duct [1]. The molecular mechanisms of renal sodium avidity have been elucidated recently. The hydrolytic and transport activities of Na,KATPase are increased 2-fold in the cortical collecting duct of PAN nephrotic rats [2,3]. The stimulation of Na,K-ATPase is restricted to the cortical collecting duct (CCD) [4] and is associated with decreased urinary sodium excretion, positive sodium balance and generation of ascites [5]. Moreover, a linear inverse correlation between urinary sodium excretion and CCD Na,K-ATPase activity has been observed in three different experimental models of nephrotic syndrome [5]. The Na-pump stimulation relies on increased synthesis and basolateral plasma membrane delivery of Na,K-ATPase subunits [4]. Indeed, the proportional increase in Na,K-ATPase activity, cell surface expression and total cellular content is associated with increased amounts of a and b subunit mRNAs in CCDs from PAN nephrotic rats [4]. In addition to the stimulation of Na,K-ATPase activity, amiloride-sensitive transepithelial voltage and sodium transport measured by in vitro microperfusion are increased in CCDs from PAN nephrotic rats [6]. Patch–clamp analysis of the apical membrane of CCD principal cells from PAN nephrotic rats revealed increased ENaC activity in the absence of transcriptional induction of the mRNAs encoding any of the three ENaC subunits [7]. To summarize, sodium retention in the nephrotic syndrome takes place in the CCD and relies on a coordinated overactivity of Na,K-ATPase and ENaC. The renal sodium retention should normally be counterbalanced by enhanced secretion of sodium in the inner medullary collecting duct, brought about by the release of atrial natriuretic peptide (ANP). This regulatory pathway is curtailed in patients and rats with nephrotic syndrome by enhanced catabolism of cyclic GMP following phosphodiesterase activation [8].