Vasopressin directly regulates cyst growth in polycystic kidney disease

Abstract

The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.

Figure 1.

Body and kidney weights, indices of cystic disease severity, renal cAMP, and urine output, in 10-wk-old (A) and 20-wk-old (B) PCK AVP^+/+, PCK AVP^+/−, and PCK AVP^−/− rats. Two-way ANOVA P values for AVP gene and gender effect are shown above the bar graphs. *P < 0.05, ^†P < 0.01, and ^‡P < 0.001 versus PCK AVP^+/+ rats.

Figure 2.

(A) Representative hematoxylin- and eosin-stained kidney sections from 10- and 20-wk-old male and female PCK AVP^+/+, PCK AVP^+/−, and PCK AVP^−/− rats. PCK AVP^−/− kidneys exhibit nearly complete protection from cystic disease. (B) Western blot of total and phosphorylated ERK1/2 and glyceraldehyde-3-phosphate dehydrogenase. ERK1/2 phosphorylation is significantly reduced in PCK AVP^−/− compared with PCK AVP^+/+ kidneys. (C) Hematoxylin- and eosin-stained kidney sections from male and female PCK AVP^−/− and PCK AVP^+/+ rats (n = 4 for each genotype and gender) treated continuously with dDAVP (10 ng/h per 100 g body wt) or vehicle alone between 12 and 20 wk of age. The administration of dDAVP recovered the cystic phenotype of the PCK AVP^−/− and aggravated the cystic disease of the PCK AVP^+/+ rats. (D) Representative photomicrographs of papilla, inner medulla, outer medulla, and cortex from male PCK AVP^−/− rats treated continuously with vehicle (a through d) or dDAVP (e through h) between 12 and 20 wk of age. Note the mild focal dilation of collecting ducts in animals treated with vehicle alone. Administration of dDAVP results in diffuse dilation of collecting ducts, which is particularly prominent in the outer medulla and cortex. Magnification, ×100 (hematoxylin and eosin).

Figure 3.

Effects of continuous subcutaneous administration of dDAVP (10 ng/h per 100 g body wt) or vehicle alone from 12 to 20 wk of age on body and kidney weights, urine output, indices of cystic disease severity, and laboratory parameters in PCK AVP^−/− and PCK AVP^+/+ rats. The administration of dDAVP recovered the cystic phenotype of the PCK AVP^−/− and aggravated the cystic disease of the PCK AVP^+/+ rats. *P < 0.05, ^†P < 0.01, and ^‡P < 0.001 versus control rats receiving vehicle alone.