Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma

Xie, Junyi; Zhang, Shungang; Cui, Xiaoyu; Zhang, Jue; Yu, Hui; Khalaf, Fatimah K.; Malhotra, Deepak; Kennedy, David J.; Shapiro, Joseph I.; Tian, Jiang

doi:10.1093/ndt/gfx334

Cited by 15 publications

(17 citation statements)

References 51 publications

(66 reference statements)

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“…The NKA is the driving power for renal Na + reabsorption and is therefore critically involved in the control of extracellular volume and blood pressure [ 21 , 22 , 23 ]. The NKA consists of two noncovalently linked polypeptides, the catalytic α subunit (≈110 kDa) and the glycosylated β (≈35 kDa) subunit, and a third recently discovered subunit, the γ (≈10 kDa) subunit, which is a member of the FXYD proteins [ 24 ]. The α subunit holds both the ATP and the ligand binding sites, and regulates ATP hydrolysis.…”

Section: Structure and Function Of The Na + /K mentioning

confidence: 99%

“…Our group has also reported a novel signaling mechanism involving CD40 regulation by NKA [ 24 ]. CD40 is a membrane glycoprotein and member of tumor necrosis factor receptor superfamily and expressed on a variety of cells including B-lymphocytes, macrophages and monocytes, dendritic cells, and endothelial cells [ 139 ].…”

Section: Novel Signaling Partners Of the Nka In Inflammation And Fmentioning

confidence: 99%

“…CD40 receptor activation on the proximal tubular epithelium of the kidney contributes to fibrosis and inflammation in various models of kidney injury [ 142 ]. Xie and colleagues showed that knockdown of the α1 subunit of NKA leads to reduced expression of CD40, while rescue of the α1 subunit restores CD40 expression in renal epithelial cells [ 24 ]. Disruption of the NKA-Src complex also interrupts CD40 signaling.…”

Section: Novel Signaling Partners Of the Nka In Inflammation And Fmentioning

confidence: 99%

“… Summary of novel signaling interactions identified between the NKA and other cell surface receptors in renal epithelial and immune cell types [ 14 , 24 , 56 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ]. …”

Section: Figurementioning

confidence: 99%

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Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Khalaf

Dube

Mohamed

et al. 2018

IJMS

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In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

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Section: Structure and Function Of The Na + /K mentioning

confidence: 99%

Section: Novel Signaling Partners Of the Nka In Inflammation And Fmentioning

confidence: 99%

Section: Novel Signaling Partners Of the Nka In Inflammation And Fmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Khalaf

Dube

Mohamed

et al. 2018

IJMS

Self Cite

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“…While the exact pathways which accelerate CKD have not been fully elucidated, it is believed that pro-inflammatory and pro-fibrotic mechanisms dominate in this setting [ 43 , 44 ]. To be sure, the Na + /K + -ATPase is a key signaling molecule involved in a number of inflammatory conditions in both human and animal models [ 19 , 45 , 46 , 47 , 48 ]. The association of CTS with inflammatory markers is not without precedent.…”

Section: Discussionmentioning

confidence: 99%

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways

Kennedy

Khalaf

Sheehy

et al. 2018

IJMS

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Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

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Six Decades of History of Hypertension Research at the University of Toledo: Highlighting Pioneering Contributions in Biochemistry, Genetics, and Host-Microbiota Interactions

2022

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Purpose of Review The study aims to capture the history and lineage of hypertension researchers from the University of Toledo in Ohio and showcase their collective scientific contributions dating from their initial discoveries of the physiology of adrenal and renal systems and genetics regulating blood pressure (BP) to its more contemporary contributions including microbiota and metabolomic links to BP regulation. Recent Findings The University of Toledo College of Medicine and Life Sciences (UTCOMLS), previously known as the Medical College of Ohio, has contributed significantly to our understanding of the etiology of hypertension. Two of the scientists, Patrick Mulrow and John Rapp from UTCOMLS, have been recognized with the highest honor, the Excellence in Hypertension award from the American Heart Association for their pioneering work on the physiology and genetics of hypertension, respectively. More recently, Bina Joe has continued their legacy in the basic sciences by uncovering previously unknown novel links between microbiota and metabolites to the etiology of hypertension, work that has been recognized by the American Heart Association with multiple awards. On the clinical research front, Christopher Cooper and colleagues lead the CORAL trials and contributed importantly to the investigations on renal artery stenosis treatment paradigms. Hypertension research at this institution has not only provided these pioneering insights, but also grown careers of scientists as leaders in academia as University Presidents and Deans of Medical Schools. Through the last decade, the university has expanded its commitment to Hypertension research as evident through the development of the Center for Hypertension and Precision Medicine led by Bina Joe as its founding Director. Summary Hypertension being the top risk factor for cardiovascular diseases, which is the leading cause of human mortality, is an important area of research in multiple international universities. The UTCOMLS is one such university which, for the last 6 decades, has made significant contributions to our current understanding of hypertension. This review is a synthesis of this rich history. Additionally, it also serves as a collection of audio archives by more recent faculty who are also prominent leaders in the field of hypertension research, including John Rapp, Bina Joe, and Christopher Cooper, which are cataloged at Interviews.

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Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma

Cited by 15 publications

References 51 publications

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways

Six Decades of History of Hypertension Research at the University of Toledo: Highlighting Pioneering Contributions in Biochemistry, Genetics, and Host-Microbiota Interactions

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