Effects of hydration in rats and mice with polycystic kidney disease

Abstract

Hopp K, Wang X, Ye H, Irazabal MV, Harris PC, Torres VE. Effects of hydration in rats and mice with polycystic kidney disease. Am J Physiol Renal Physiol 308: F261-F266, 2015. First published December 10, 2014 doi:10.1152/ajprenal.00345.2014.-Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C (Pkd1 RC/RC ) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1 RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-D-arginine vasopressin, as previously shown for Pkd1 RC/RC mice and confirmed here in Pkd2 WS25/Ϫ mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models. polycystic kidney disease; vasopressin; cAMP; cyclic nucleotide phosphodiesterase; hydration POLYCYSTIC KIDNEY DISEASES (PKDs) are characterized by the development and growth of cysts arising from renal tubules and associated with enlargement of the kidneys and destruction of the renal parenchyma. Autosomal dominant PKD (AD-PKD), the fourth leading cause of end-stage kidney disease in adults, is caused by mutations to either of two genes, PKD1 or PKD2. Autosomal recessive PKD (ARPKD), an important cause of end-stage renal disease and mortality in infants and children, is caused by mutations to polycystic kidney and hepatic disease 1 (PKHD1) (9,23).A large body of evidence indicates that vasopressin and V2 receptor signaling promote the progression of PKD via cAMP and PKA (22). Administration of the V2 receptor agonist 1-deamino-8-D-arginine vasopressin (DDAVP) aggravates the disease in orthologous models of ARPKD and PKD1 (10,28). Genetic elimination of circulating vasopressin markedly inhibits the development of PKD in PCK rats, an effect that was reversed by the administration of DDAVP (28). Treatment with select...

Modulation of Polycystic Kidney Disease Severity by Phosphodiesterase 1 and 3 Subfamilies

“…35 PCK rats exhibit renal cysts at or soon after birth, whereas most mouse Pkhd1 knockouts only develop renal cysts at an advanced age or not at all. The renal phenotype of Pkd1 or Pkd2 heterozygous knockout mice is similarly normal or very mild.…”

“…35 A possible explanation for the different susceptibility of mice and rats to the development of PKD and the cystogenic effects of DDAVP could be the higher PDE activities reported in kidneys from mice compared with those from rats. 16,17 To test this hypothesis, we administered DDAVP (30 ng/100 g body wt per hour subcutaneously using a osmotic minipump) to and Pkd2 2 /WS25 ;Pde3b 2 /2 mice had slightly higher body and liver weights but no increase in liver cystic or fibrotic indices.…”

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

“…The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduced cyst burden and protected kidney function in rodent models of the disease (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

“…4 Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP). 5,6 The suppression of vasopressin production, release, or action by means of hydration, 7,8 V 2 -receptor blockade, [9][10][11][12][13][14] or genetic mutation 15 has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models.…”