Sildenafil reduces polyuria in rats with lithium-induced NDI

Abstract

Sanches TR, Volpini RA, Massola Shimizu MH, de Bragança AC, Oshiro-Monreal F, Seguro AC, Andrade L. Sildenafil reduces polyuria in rats with lithium-induced NDI. Am J Physiol Renal Physiol 302: F216 -F225, 2012. First published October 12, 2011 doi:10.1152/ajprenal.00439.2010.-Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na ϩ /H ϩ exchanger 3 (NHE3), Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC2), epithelial Na channel (ENaC; ␣-, ␤-, and ␥-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (LiϩSil). In LiϩSil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the LiϩSil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in LiϩSil rats, AQP2 expression was partially normalized, whereas that of UT-A1, ␥-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Liinduced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.aquaporin-2; diabetes insipidus; urea transporter; sodium transporters LITHIUM (Li) has been widely used as a pharmacological agent in psychiatric therapy and is the established drug of choice for treating bipolar affective disorders (20,21,29,31). It is eliminated primarily through renal excretion and competes with the Na-K-2Cl cotransporter (NKCC2) and the epithelial sodium channel (ENaC) (12,13,39). In addition, Li is transported by Na-K-ATPase (12,13,39). Approximately 60% of the filtered load of Li is reabsorbed in the proximal tubule, whereas 20% is reabsorbed in the thick ascending limb, connecting tubule, and cortical collecting duct (12, 13). Nephrogenic diabetes insipidus (NDI), increased urinary excretion of sodium (UVNa), and distal renal tubular acidosis have all been associated with Li treatment (16,17,22,31). In particular, Li-induced NDI is associated with dysregulation of aquaporin-2 (AQP2) and ENaC in the collecting duct (20,22,23,26,41). Furthermore, reduced urine concentrating ability has been shown to accompany decreased expression of th...

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

“…Therefore, additional strategies have been developed in an attempt to increase trafficking, abundance, and accumulation of AQP2 on the apical membrane of collecting tubules to promote water reabsorption. 50 Some of these potential therapeutic strategies included activating the cAMP pathway using calcitonin to increase cAMP levels via GaS activation, 11 stimulating the nitric oxide/cGMP pathway with the phosphodiesterase inhibitor sildenafil, 13,51 affecting the PGE2 pathway using the COX-2 inhibitor celecoxib, 52,53 or modulating the actin cytoskeleton network with statins to decrease AQP2 endocytosis. 9,10 These approaches seem promising, but perhaps because lithium exerts such a complex effect on AQP2 trafficking and collecting duct morphology, none of them have yet been shown to provide sustainable benefits in patients.…”

Diabetes Insipidus: A Review

“…Another potential treatment of hereditary NDI being investigated is the use of phosphodiesterase (PDE) inhibitors, used to increase intracellular cAMP levels in the renal cells. Animal studies have showed that the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil increase urine concentration [136,137].…”

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus

“…Although, administration of sildenafil citrate to rats has been shown to result in AQP2 membrane accumulation in principal cells in the absence of vasopressin signaling via its G-protein-coupled receptor (V2R), it has not yet been evaluated for the treatment of NDI in human subjects [20,21] .…”