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Na,K-ATPase signaling in cyst progression in autosomal dominant polycystic kidney disease
Trant, Jordan
Trant, Jordan
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Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic disorder of the kidney, affecting 1:500-1000 live births across the world. It is characterized by the formation and growth of fluid-filled cysts which grow larger throughout the lifetime of the patient, eventually compressing the renal tissue and leading to pain, impaired kidney function, and eventual renal failure. Though it is known that mutations in PKD1 or PKD2, genes which encode the proteins polycystin-1 and polycystin-2, respectively, cause ADPKD, it is not known how alterations of either these proteins lead to cyst development and growth. Further, the progression of ADPKD is highly variable, even among patients with the same mutation, suggesting a strong environmental component to ADPKD pathogenesis.
One factor which has been shown to increase ADPKD progression is the hormone ouabain. Ouabain is a cardiotonic steroid (CTS) that circulates normally within mammals. It and other CTS compounds are obtained through the diet and produced as endogenous hormones, with normal functions including cell proliferation and hypertrophy, control of cardiac inotropy, chronotropy, and blood pressure, and renal sodium handling. The receptor for CTS is the ubiquitous membrane protein, Na,K-ATPase (NKA). NKA has a primary function of maintaining cellular ion gradients through ATP-fueled movement of Na+ and K+ across the membrane; however, it is also the receptor and signal transducer for ouabain and other CTS.
It has been shown that a subset of NKA within ADPKD cells has abnormally high affinity for ouabain which causes excessive stimulation of the NKA signaling pathway. Within ADPKD cells, this manifests as an increase in cell proliferation, fluid secretion, apoptosis, and epithelial to mesenchymal transition (EMT). The goal of this work was to expand these cell-based studies into in vivo models of ADPKD, provide further evidence for the role of ouabain in ADPKD progression, and further characterize NKA signaling and its role in ADPKD. We found that, similar to ADPKD cells in culture, physiological levels of ouabain in ADPKD mice causes progression of the disease by increasing cystic area, cyst number, kidney fibrosis, and cell proliferation. Further, by using a mouse model which ubiquitously expresses a mutant form of NKA with increased affinity for ouabain, we showed that the NKA ouabain affinity is critical for the effects of ouabain in ADPKD. Mechanistically, ouabain increases the activation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), two pathways which are upregulated in ADPKD but further stimulated by ouabain binding to NKA.
We hypothesized that cell caveolae, as an important structure facilitating NKA signaling, would likewise be important for the transmission of ouabain’s effects in ADPKD. We found that in ADPKD mice lacking caveolae, ouabain was no longer able to increase cystic area, kidney fibrosis, or cell proliferation; the ouabain-induced increases in the activation of ERK and Akt were also absent. Interestingly, caveolar deletion also removed the high ouabain affinity subset of NKA, and all NKA in the kidneys of these mice exhibited the normal, low ouabain affinity expected of mouse NKA. In summary, we found that ouabain stimulates ADPKD progression in vivo as it does in vitro, and through similar mechanisms. Moreover, NKA affinity for ouabain is linked to this effect, as changing all NKA to have a high ouabain affinity significantly worsens ADPKD and removing the high ouabain affinity pool through caveolar deletion ablates ouabain’s effects on disease progression. Finally, we showed that caveolae are essential for NKA signaling and ouabain-induced cyst progression in ADPKD mice. A more thorough understanding what causes a change in NKA ouabain affinity in ADPKD and the role of NKA signaling within the disease is needed for the development of potential therapeutics to stop or slow ADPKD progression.
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2025-01-01
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University of Kansas
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Keywords
Molecular biology, ADPKD, Cell signaling, NaK-ATPase, NaK-ATPase signaling