Ouabain enhances renal cyst growth in a slowly progressive mouse model of autosomal dominant polycystic kidney disease

Am J Physiol Renal Physiol. 2023 Oct 12. doi: 10.1152/ajprenal.00056.2023. Online ahead of print.ABSTRACTRenal cyst progression in autosomal dominant polycystic kidney disease (ADPKD) is highly dependent on agents circulating in blood. We have previously shown, using different in vitro models, that one of these agents is the hormone ouabain. By binding to Na,K-ATPase (NKA), ouabain triggers a cascade of signal transduction events which enhance ADPKD cyst progression by stimulating cell proliferation, fluid secretion, and dedifferentiation of the renal tubular epithelial cells. Here, we determined the effects of ouabain in vivo. We show that daily administration of ouabain to Pkd1RC/RC ADPKD mice for 1-5 months, at physiological levels, augmented kidney cyst area and number compared to saline-injected controls. Also, ouabain favored renal fibrosis; however, renal function was not significantly altered as determined by blood urea nitrogen (BUN) levels. Ouabain did not have a sex preferential effect, with male and female mice being affected equally. By contrast, ouabain had no significant effect on wild type mice. Additionally, the actions of ouabain on Pkd1RC/RC mice were exacerbated when another mutation that increased the affinity of Na,K-ATPase for ouabain was introduced to the mice (Pkd1RC/RCNKAα1OS/OS mice). Altogether, this work highlights the role of ouabain as a pro-cystogenic factor in the development of ADPKD in vivo; that the ouabain affinity site on NKA is critical...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Source Type: research