In experimental preascitic liver cirrhosis calcium-dependent diuretic systems are downregulated, but may be normalized by specific metabolic and pharmacologic stimuli

Abstract

Extracellular Ca2+ stimulates cell membrane receptors called calcium-sensing receptors (CaRs) leading to enhanced renal tubule production of PGE2, which in turn decreases both sodium reabsorption in the thick ascending limb (TAL) of Henle's loop and free-water reabsorption in collecting ducts [ 1 Am J Physiol 273;1997:F421–9. Google Scholar , 2 J Clin Invest 99;1997:1399–405. Google Scholar ]. Parathyroid hormone (PTH) increases expression of CaRs in the kidney and reduces Na+-K+-2Cl− cotransporter (BSC-1) expression in TAL cells [ [3] Am J Physiol 286;2004:F534–45. Google Scholar ]. To assess the activity of this Ca2+-dependent diuretic system in experimental preascitic cirrhosis we evaluated renal function, plasma levels of active renin, aldosterone and vasopressin, PGE2-urinary excretion, and renal tissue concentrations of BSC-1 and CaRs in four groups of rats: 10 control rats receiving i.v. 5% glucose solution (vehicle), and three groups of 10 rats with CCl4-induced preascitic cirrhosis receiving vehicle or 0.5 mg i.v. poly-l-arginine (PLA), a CaR-selective agonist [ [4] Am J Physiol 281;2001:F658–64. Google Scholar ], or 5 subcutaneous doses of 3 mcg/kg PTH (one dose every 12 h before the study). The amount of vehicle infused prior to determinations was the same in each group. When compared to controls, cirrhotic rats showed reduced urine volume and absolute and fractional excretion rate of sodium (P < 0.05). Western blot analysis revealed significantly reduced CaR and increased BSC-1 protein content in kidney parenchyma of cirrhotic rats with respect to controls (all P < 0.001). Both PTH-treated and PLA-treated cirrhotic rats had their urine and sodium excretion rates normalized (all P < 0.03 versus cirrhotic rats receiving vehicle); both treatments also increased renal plasma flow, PGE2 urinary excretion, and free-water clearance in cirrhotic rats with respect to untreated cirrhotic animals (all P < 0.01). Moreover, PTH reduced BSC-1 and augmented CaR expression in the kidney of cirrhotic rats (all P < 0.001). In summary, in preascitic cirrhosis sodium and fluid retention may be linked to significant downregulation of renal CaRs and upregulation of tubular sodium retaining channels. Both metabolic (hyperparathyroidism) and pharmacologic (PLA) stimuli return these changes to normality.