Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation

Chronic kidney disease has multiple etiologies, but its single, hallmark lesion is renal fibrosis. CD39 is a key purinergic enzyme in the hydrolysis of ATP and increased CD39 activity on regulatory T cells (Treg) is protective in adriamycin-induced renal fibrosis. We examined the effect of overexpression of human CD39 on the development of renal fibrosis in the unilateral ureteric obstructive (UUO) model, a model widely used to study the molecular and cellular factors involved in renal fibrosis. Mice overexpressing human CD39 (CD39Tg) and their wild-type (WT) littermates were subjected to UUO; renal histology and messenger RNA (mRNA) levels of adenosine receptors and markers of renal fibrosis were examined up to 14 days after UUO. There were no differences between CD39Tg mice and WT mice in the development of renal fibrosis at days 3, 7, and 14 of UUO. Relative mRNA expression of the adenosine A 2A receptor and endothelin-1 were higher in CD39Tg than WT mice at day 7 post UUO, but there were no differences in markers of fibrosis. We conclude that human CD39 overexpression does not attenuate the development of renal fibrosis in the UUO model. The lack of protection by CD39 overexpression in the UUO model is multifactorial due to the different effects of adenosinergic receptors on the development of renal fibrosis.

Section: Methods Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Roberts

Lü

Chia

et al. 2016

“…Deletion of NTPDase1 in mice revealed a key role of this enzyme in the prevention of thrombosis [41,42], in purine signaling in angiogenesis [174], vascular permeability [175,176], vascular relaxation [49], in the control of macrophage function [177], or also in promoting tumor growth [178]. Accordingly, transgenic mice expressing human NTPDase1 exhibited impaired platelet aggregation and were protected from thrombosis in a transplantation setting [179]. Moreover, adenovirus-mediated gene transfer of human placental NTPDase1 [91] into vascular smooth muscle cells was found to suppress thrombus formation and subsequent neointimal growth [180].…”

Section: Downstream Signaling Nucleotidesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

888

922

Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

“…IRI has been increasingly recognized as an important source of morbidity and mortality in a number of clinical disorders, including hepatic and intestinal ischemia, acute renal injury, cardiac and cerebrovascular disease, shock and organ transplantation [24][25][26][27][28]. Previously, data has been published showing the deleterious effect of CD39 deletion on intestinal, myocardial, and renal ischemia as well as the crucial impact of CD39 on IP of these organs [24,25,28].…”

Section: Discussionmentioning

confidence: 99%

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

Sun

Imai

Nowak-Machen

et al. 2011

Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5′-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/−) and matched Cd39-null mice (−/−); (n=25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n=6) and Cd39-null mice (n=6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P 31 -NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/− and 84% of Cd39-null mice required euthanasia or died within 4 h postreperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.