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Query: UMLS:C0020538 (
hypertension
)
170,190
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Renal angiotensin II (AII) is suggested to play a role in the enhanced sodium reabsorption that causes a shift in pressure natriuresis in obesity related
hypertension
; however, the mechanism is not known. Therefore, to assess the influence of AII on tubular sodium transport, we determined the effect of AII on the Na+, K+-ATPase activity (NKA), an active transporter regulated by the AT1 receptor activity, in the isolated proximal tubules of lean and obese Zucker rats. Also, we determined the levels of the tubular AT1 receptor and associated signal transducing G proteins, as the initial signaling components that mediate the effects of AII on Na+, K+-ATPase activity. In the isolated proximal tubules, AII produced greater stimulation of the NKA activity in obese compared with lean rats. Determination of the AT1 receptors by Scatchard analysis of the [125I] Sar-Ang II binding and Western blot analysis in the basolateral (
BLM
) and brush border membrane (BBM) revealed a modest but significant increase (23%) in the AT1 receptor number mainly in the
BLM
of obese compared with lean rats. The AII affinity for AT1 receptors, as determined by IC50 values of AII to displace [125I] Sar-Ang II binding in
BLM
and BBM were similar in lean and obese rats. Western blot analysis revealed significant increases in Gialpha1, Gialpha2, Gialpha3, and Gq/11alpha in
BLM
and Gialpha1, Gialpha3, and Gq/11alpha in BBM of obese as compared with lean rats. The increase in the levels of the AT1 receptor and G proteins, mainly in the
BLM
, may be contributing to the enhanced AII-induced activation of NKA in the proximal tubules of obese rats. This phenomenon, in part, may be responsible for the increased sodium reabsorption and the development of
hypertension
in obese Zucker rats.
...
PMID:Enhanced angiotensin II-induced activation of Na+, K+-ATPase in the proximal tubules of obese Zucker rats. 1644 62
Background:
Pulmonary hypertension (PH) is a devastating and progressive disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and remodeling of the lung vasculature. Adenosine signaling through the ADORA2B receptor has previously been implicated in disease progression and tissue remodeling in chronic lung disease. In experimental models of PH associated with chronic lung injury, pharmacological or genetic inhibition of ADORA2B improved markers of chronic lung injury and hallmarks of PH. However, the contribution of ADORA2B expression in the PASMC was not fully evaluated.
Hypothesis:
We hypothesized that adenosine signaling through the ADORA2B receptor in PASMC mediates the development of PH.
Methods:
PASMCs from controls and patients with idiopathic pulmonary arterial
hypertension
(iPAH) were characterized for expression levels of all adenosine receptors. Next, we evaluated the development of PH in ADORA2B
f/f
-Transgelin (Tagln)
cre
mice. These mice or adequate controls were exposed to a combination of SUGEN (SU5416, 20 mg/kg/b.w. IP) and hypoxia (10% O
2
) for 28 days (HX-SU) or to chronic low doses of bleomycin (
BLM
, 0.035U/kg/b.w. IP). Cardiovascular readouts including right ventricle systolic pressures (RVSPs), Fulton indices and vascular remodeling were determined. Using PASMCs we identified ADORA2B-dependent mediators involved in vascular remodeling. These mediators: IL-6, hyaluronan synthase 2 (HAS2) and tissue transglutaminase (Tgm2) were determined by RT-PCR and validated in our HX-SU and
BLM
models.
Results:
Increased levels of ADORA2B were observed in PASMC from iPAH patients. ADORA2B
f/f
-Tagln
cre
mice were protected from the development of PH following HX-SU or
BLM
exposure. In the
BLM
model of PH, ADORA2B
f/f
- Tagln
cre
mice were not protected from the development of fibrosis. Increased expression of IL-6, HAS2 and Tgm2 was observed in PASMC in an ADORA2B-dependent manner. These mediators were also reduced in ADORA2B
f/f
- Tagln
cre
mice exposed to HX-SU or
BLM
.
Conclusions:
Our studies revealed ADORA2B-dependent increased levels of IL-6, hyaluronan and Tgm2 in PASMC, consistent with reduced levels in ADORA2B
f/f
- Tagln
cre
mice exposed to HX-SU or
BLM
. Taken together, our data indicates that ADORA2B on PASMC mediates the development of PH through the induction of IL-6, hyaluronan and Tgm2. These studies point at ADORA2B as a therapeutic target to treat PH.
...
PMID:Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension. 2991 Jul 35
