Medicine and Health Sciences Commons^™

Rapamycin Attenuates Cardiac Fibrosis In Experimental Uremic Cardiomyopathy By Reducing Marinobufagenin Levels And Inhibiting Downstream Pro-Fibrotic Signaling, Steven T. Haller Phd, Yanling Yan Phd, Christopher A. Drummond Phd, Joe Xie Md, Jiang Tian Phd, David J. Kennedy Phd, Victoria Y. Shilova Phd, Zijian Xie Phd, Jiang Liu Phd, Christopher J. Cooper Md, Deepak Malhotra Md, Phd, Joseph I. Shapiro Md, Olga V. Fedorova Phd, Alexei Y. Bagrov Md, Phd

Yanling Yan

Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K‐ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway.

Methods and Results: Biosynthesis of MBG by cultured human JEG‐3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 …

Attenuation Of Na/K-Atpase Mediated Oxidant Amplification With Pnaktide Ameliorates Experimental Uremic Cardiomyopathy, Jiang Liu, Jiang Tian, Muhammad Chaudhry, Kyle Maxwell, Yanling Yan, Xiaoliang Wang, Preeya T. Shah, Asad A. Khawaja, Rebecca Martin, Tylor J. Robinette, Adee El-Hamdani, Michael W. Dodrill, Komal Sodhi, Christopher A. Drummond, Steven T. Haller, David J. Keenedy, Nader G. Abraham, Zijian Xie, Joseph I. Shapiro Md

Yanling Yan

We have previously reported that the sodium potassium adenosine triphosphatase (Na/K-ATPase) can effect the amplification of reactive oxygen species. In this study, we examined whether attenuation of oxidant stress by antagonism of Na/K-ATPase oxidant amplification might ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy (PNx). PNx induced the development of cardiac morphological and biochemical changes consistent with human uremic cardiomyopathy. Both inhibition of Na/K-ATPase oxidant amplification with pNaKtide and induction of heme oxygenase-1 (HO-1) with cobalt protoporphyrin (CoPP) markedly attenuated the development of phenotypical features of uremic cardiomyopathy. In a reversal study, administration of pNaKtide after the induction of uremic …

Protein Carbonylation Of An Amino Acid Residue Of The Na/K‐Atpase Α1 Subunit Determines Na/K‐Atpase Signaling And Sodium Transport In Renal Proximal Tubular Cells, Yanling Yan, Anna P. Shapiro, Brahma R. Mopidevi, Muhammad Chaudhry, Kyle Maxwell, Steven T. Haller, Christopher A. Drummond, David J. Keendey, Jiang Tian, Deepak Malhorta, Zijian Xie, Joseph I. Shapiro Md, Jiang Liu

Yanling Yan

Background We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K‐ATPase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K‐ATPase α1 subunit, reactive oxygen species are required for ouabain‐stimulated Na/K‐ATPase/c‐Src signaling and subsequent regulation of active transepithelial ²²Na⁺ transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K‐ATPase signaling and sodium handling.

Methods and Results Stable pig α1 knockdown LLC‐PK1‐originated PY‐17 cells were rescued by expressing wild‐type rat α1 and rat α1 with …

Carbonylationmodificationregulatesna/K-Atpasesignalingandsaltsensitivity:Areviewandahypothesis, Preeya Shah Phd, Rebecca Martin, Yanling Yan, Joseph I. Shapiro Md, Jiang Liu

Yanling Yan

Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions. Accumulating evidence indicates that oxidative stress not only regulates the Na/K-ATPase enzymatic activity, but also regulates its signaling and other functions. While cardiotonic steroids (CTS)-induced increase in reactive oxygen species (ROS) generation is an intermediate step in CTS-mediated Na/K-ATPase signaling, increase in ROS alone also stimulates Na/K-ATPase signaling. Based on literature and our observations, we hypothesize that ROS have biphasic effects on Na/K-ATPase signaling, transcellular sodium transport, and urinary sodium excretion. Oxidative modulation, in particular site specific carbonylation of the Na/K-ATPase α1 subunit, is a critical step in proximal …

The Physiological And Clinical Importance Of Sodium Potassium Atpase In Cardiovascular Diseases, Yanling Yan, Joseph I. Shapiro Md

Yanling Yan

The Na/K-ATPase has been extensively studied, but it is only recently that its role as a scaffolding and signaling protein has been identified. It has been identified that cardiotonic steroids (CTS) such as digitalis mediate signal transduction through the Na/K-ATPase in a process found to result in the generation of reactive oxygen species (ROS). As these ROS also appear capable of initiating this signal cascade, a feed forward amplification process has been postulated and subsequently implicated in some disease pathways including uremic cardiomyopathy.

Na/K-Atpase Signaling And Salt Sensitivity: The Role Of Oxidative Stress, Jiang Liu, Yanling Yan, Ying Nie

Yanling Yan

Other than genetic regulation of salt sensitivity of blood pressure, many factors have been shown to regulate renal sodium handling which contributes to long-term blood pressure regulation and have been extensively reviewed. Here we present our progress on the Na/K-ATPase signaling mediated sodium reabsorption in renal proximal tubules, from cardiotonic steroids-mediated to reactive oxygen species (ROS)-mediated Na/K-ATPase signaling that contributes to experimental salt sensitivity.

Involvement Of Reactive Oxygen Species In A Feed-Forward Mechanism Of Na/K-Atpase Mediated Signaling, Yanling Yan, Anna P. Shapiro, Steven Haller, Vinal Katragadda, Lijun Liu, Jiang Tian, Venkatesha Basrur, Deepak Malhotra, Zi-Jian Xie, Nader G. Abraham, Joseph I. Shapiro Md, Jiang Liu

Yanling Yan

Cardiotonic steroids (such as ouabain) signaling through Na/K-ATPase regulate sodium reabsorption in the renal proximal tubule. We report here that reactive oxygen species are required to initiate ouabain-stimulated Na/K-ATPase·c-Src signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine prevented ouabain-stimulated Na/K-ATPase·c-Src signaling, protein carbonylation, redistribution of Na/K-ATPase and sodium/proton exchanger isoform 3, and inhibition of active transepithelial ²²Na⁺ transport. Disruption of the Na/K-ATPase·c-Src signaling complex attenuated ouabain-stimulated protein carbonylation. Ouabain-stimulated protein carbonylation is reversed after removal of ouabain, and this reversibility is largely independent of de novo protein synthesis and degradation by either the lysosome or the proteasome pathways. Furthermore, …

Pnaktide Inhibits Na/K-Atpase Reactive Oxygen Species Amplification And Attenuates Adipogenesis, Komal Sodhi, Kyle Maxwell, Yanling Yan, Jiang Liu, Muhammad Chaudhry, Morgan Getty, Zijian Xie, Nader G. Abraham, Joseph I. Shapiro Md

Yanling Yan

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose-dependent manner. Complementary experiments in C57Bl6 mice fed …