On the Many Actions of Ouabain: Pro-Cystogenic Effects in Autosomal Dominant Polycystic Kidney Disease

Abstract

Ouabain and other cardenolides are steroidal compounds originally discovered in plants. Cardenolides were first used as poisons, but after finding their beneficial cardiotonic effects, they were rapidly included in the medical pharmacopeia. The use of cardenolides to treat congestive heart failure remained empirical for centuries and only relatively recently, their mechanisms of action became better understood. A breakthrough came with the discovery that ouabain and other cardenolides exist as endogenous compounds that circulate in the bloodstream of mammals. This elevated these compounds to the category of hormones and opened new lines of investigation directed to further study their biological role. Another important discovery was the finding that the effect of ouabain was mediated not only by inhibition of the activity of the Na,K-ATPase (NKA), but by the unexpected role of NKA as a receptor and a signal transducer, which activates a complex cascade of intracellular second messengers in the cell. This broadened the interest for ouabain and showed that it exerts actions that go beyond its cardiotonic effect. It is now clear that ouabain regulates multiple cell functions, including cell proliferation and hypertrophy, apoptosis, cell adhesion, cell migration, and cell metabolism in a cell and tissue type specific manner. This review article focuses on the cardenolide ouabain and discusses its various in vitro and in vivo effects, its role as an endogenous compound, its mechanisms of action, and its potential use as a therapeutic agent; placing especial emphasis on our findings of ouabain as a pro-cystogenic agent in autosomal dominant polycystic kidney disease (ADPKD).

Skeletal Muscle Na,K-ATPase as a Target for Circulating Ouabain

“…This ion translocation activity underlies the resting membrane potential (RMP) as well as membrane excitability and provides the driving force for secondary ion transport [1]. In addition to its "classical" role in ion transport, the Na,K-ATPase is now considered as one of the most important signaling molecules in neuronal, epithelial, cardiac and vascular tissues [2][3][4].…”

Circulating Ouabain Modulates Expression of Claudins in Rat Intestine and Cerebral Blood Vessels

“…Previous studies on MDCK II (Madin-Darby canine kidney), rat Sertoli (the key structure of blood-testis barrier) and ADPKD (autosomal dominant polycystic kidney disease) cell cultures demonstrated that nanomolar ouabain induces the expression of claudin-1, -2, -4 and -11 [20][21][22]. These studies suggest the cSrc/Erk1/2-dependent intracellular signaling that regulates epithelial phenotype and proliferation upon ouabain binding [11,[20][21][22]. We used the porcine jejunum cell line IPEC-J2, which is considered as a reliable model for studying human gastrointestinal tract [31].…”

“…The Na,K-ATPase is now considered as an important signaling molecule that can transduce ouabain binding into an activation of downstream signaling. Binding of ouabain activates the Na,K-ATPase/cSrc complex resulting in initiation of protein kinase cascades and production of second messengers that alter cellular functions in a cell-specific manner [9][10][11]. Previous studies on MDCK II (Madin-Darby canine kidney), rat Sertoli (the key structure of blood-testis barrier) and ADPKD (autosomal dominant polycystic kidney disease) cell cultures demonstrated that nanomolar ouabain induces the expression of claudin-1, -2, -4 and -11 [20][21][22].…”

“…Currently, the α1Na, K-ATPase/cSrc complex is recognized as a receptor for CTS that initiates downstream a variety of intracellular signaling pathways. Thus, the Na,K-ATPase is now considered as an important signaling molecule in neuronal, epithelial, cardiac and vascular tissues [3,[9][10][11]. It is assumed that endogenous analogues of CTS serve as physiological triggers of the Na,K-ATPase signal function.…”

Identification of a pathogenic mutation in a Chinese pedigree with polycystic kidney disease

“…PKD2 is located on chromosome 4q22.1, and its protein product, polycystin-2 (PC2), also localizes to the cell membrane, acting as a nonselective Ca 2+ channel ( 12 ). The C-termini of PC1 and PC2 interact to regulate ion transportation; thus, mutations in PKD1 and PKD2 may lead to disease ( 13 – 16 ).…”