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Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA ?-1 (Na+/K+-ATPase ?-1)/Src Complex in Renal Epithelial Cells and Immune Cells.

ABSTRACT: Cardiotonic steroids (CTSs) are NKA ?-1 (Na+/K+-ATPase ?-1) ligands that are increased in volume expanded states and associated with cardiac and renal diseases. Although initiation and resolution of inflammation is an important component of cellular injury and repair in renal disease, it is unknown whether CTS activation of NKA ?-1 signaling in this setting regulates this inflammatory response. On this background, we hypothesized that CTS signaling through the NKA ?-1-Src kinase complex promotes a proinflammatory response in renal epithelial and immune cells. First, we observed that the CTS telocinobufagin activated multiple proinflammatory cytokines/chemokines in renal epithelial cells, and these effects were attenuated after either NKA ?-1 knockdown or with a specific inhibitor of the NKA ?-1-Src kinase complex (pNaKtide). Similar findings were observed in immune cells, where we demonstrated that while telocinobufagin induced both oxidative burst and enhanced Nuclear factor kappa-light-chain-enhancer of activated B cells activation in macrophages ( P<0.05), the effects were abolished in NKA ?-1+/- macrophages or by pretreatment with pNaKtide or the Src inhibitor PP2 ( P<0.01). In a series of in vivo studies, we found that 5/6th partial nephrectomy induced significantly less oxidative stress in the remnant kidney of NKA ?-1+/- versus wild-type mice. Similarly, 5/6th partial nephrectomy yielded decreased levels of the urinary oxidative stress marker 8-Oxo-2'-deoxyguanosine in NKA ?-1+/- versus wild-type mice. Finally, we found that in vivo inhibition of the NKA ?-1-Src kinase complex with pNaKtide significantly inhibited renal proinflammatory gene expression after 5/6th partial nephrectomy. These findings suggest that the NKA ?-1-Src kinase complex plays a central role in regulating the renal inflammatory response induced by elevated CTS both in vitro and in vivo.

SUBMITTER: Khalaf FK

PROVIDER: S-EPMC6561827 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA α-1 (Na+/K+-ATPase α-1)/Src Complex in Renal Epithelial Cells and Immune Cells.

Khalaf Fatimah K FK Dube Prabhatchandra P Kleinhenz Andrew L AL Malhotra Deepak D Gohara Amira A Drummond Christopher A CA Tian Jiang J Haller Steven T ST Xie Zijian Z Kennedy David J DJ

Hypertension (Dallas, Tex. : 1979) 20190528 1

Cardiotonic steroids (CTSs) are NKA α-1 (Na<sup>+</sup>/K<sup>+</sup>-ATPase α-1) ligands that are increased in volume expanded states and associated with cardiac and renal diseases. Although initiation and resolution of inflammation is an important component of cellular injury and repair in renal disease, it is unknown whether CTS activation of NKA α-1 signaling in this setting regulates this inflammatory response. On this background, we hypothesized that CTS signaling through the NKA α-1-Src k ...[more]

PMID: 31132948

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Project description:The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2 and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose-response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase of cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio, accompanied by an increase of myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1r/rα2s/s mouse failed to do so in the α1s/sα2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.

Dataset Information

Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA ?-1 (Na+/K+-ATPase ?-1)/Src Complex in Renal Epithelial Cells and Immune Cells.

Publications

Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA α-1 (Na+/K+-ATPase α-1)/Src Complex in Renal Epithelial Cells and Immune Cells.

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