Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

The neurite outgrowth inhibitor protein Nogo is one of 300 proteins that contain a reticulon homology domain, which is responsible for their association with the endoplasmic reticulum. Here we have found that the Nogo-B spliceform becomes phosphorylated at Ser107 in response to lipopolysaccharide in RAW264 macrophages or anisomycin in HeLa cells. The phosphorylation is prevented by SB 203580, an inhibitor of SAPK2a (stress-activated protein kinase 2a)/p38α and SAPK2b/p38β, and does not occur in embryonic fibroblasts generated from SAPK2a/p38α-deficient mice. Nogo-B is phosphorylated at Ser107in vitro by MAPKAP-K2 [MAPK (mitogen-activated protein kinase)-activated protein kinase-2] or MAPKAP-K3, but not by other protein kinases that are known to be activated by SAPK2a/p38α. The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by ‘knockdown’ of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2.

Download Full-text

The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK

Molecular and Cellular Biology ◽

10.1128/mcb.01456-06 ◽

2006 ◽

Vol 27 (1) ◽

pp. 170-181 ◽

Cited By ~ 159

Author(s):

N. Ronkina ◽

A. Kotlyarov ◽

O. Dittrich-Breiholz ◽

M. Kracht ◽

E. Hitti ◽

...

Keyword(s):

Protein Kinase ◽

Tumor Necrosis Factor ◽

Protein Kinases ◽

Tumor Necrosis ◽

Mitogen Activated Protein Kinase ◽

Double Knockout ◽

Mitogen Activated Protein ◽

Deficient Mice ◽

Necrosis Factor

ABSTRACT MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

Download Full-text

Sexual Dimorphism in Periapical Inflammation and Bone Loss from Mitogen-activated Protein Kinase Phosphatase-1 Deficient Mice

Journal of Endodontics ◽

10.1016/j.joen.2012.04.016 ◽

2012 ◽

Vol 38 (8) ◽

pp. 1097-1100 ◽

Cited By ~ 11

Author(s):

Justin McAbee ◽

Qiyan Li ◽

Hong Yu ◽

Keith L. Kirkwood

Keyword(s):

Sexual Dimorphism ◽

Protein Kinase ◽

Bone Loss ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Periapical Inflammation ◽

Deficient Mice

Download Full-text

Angiotensin II blockade causes acute renal failure in eNOS-deficient mice

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/14703203010020013501 ◽

2001 ◽

Vol 2 (1_suppl) ◽

pp. S199-S203 ◽

Cited By ~ 2

Author(s):

Jürgen Schnermann ◽

Yuning G Huang ◽

Josie P Briggs

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Glomerular Filtration ◽

Vascular Resistance ◽

Knockout Mice ◽

Renal Vascular Resistance ◽

Wild Type ◽

Arteriolar Tone ◽

Renal Vascular ◽

Deficient Mice

Compared with wild-type mice, adult endothelial nitric oxide synthase (eNOS) knockout mice (eight months of age) have increased blood pressure (BP) (126±9 mmHg vs. 100±4 mmHg), and an increased renal vascular resistance (155±16 vs. 65±4 mmHg.min/ml). Renal vascular resistance responses to i.v. administration of noradrenaline were markedly enhanced in eNOS knockout mice. Glomerular filtration rate (GFR) of anaesthetised eNOS -/- mice was 324±57 µl/min gKW, significantly lower than the GFR of 761±126 µl/min.gKW in wild-type mice. AT1-receptor blockade with i.v. candesartan (1—1.5 mg/kg) reduced arterial blood pressure and renal vascular resistance, and increased renal blood flow (RBF) to about the same extent in wild-type and eNOS -/- mice. Candesartan did not alter GFR in wild-type mice (761±126 vs. 720±95 µl/min.gKW), but caused a marked decrease in GFR in eNOS -/- mice (324.5±75.2 vs. 77±18 µl/min.gKW). A similar reduction in GFR of eNOS deficient mice was also caused by angiotensin-converting enzyme (ACE) inhibition. Afferent arteriolar granularity, a measure of renal renin expression, was found to be reduced in eNOS -/- compared with wild-type mice. In chronically eNOS-deficient mice, angiotensin II (Ang II) is critical for maintaining glomerular filtration pressure and GFR, presumably through its effect on efferent arteriolar tone.

Download Full-text

Reduced autoregulatory effectiveness in adenosine 1 receptor-deficient mice

AJP Renal Physiology ◽

10.1152/ajprenal.00381.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. F888-F891 ◽

Cited By ~ 30

Author(s):

S. Hashimoto ◽

Y. Huang ◽

J. Briggs ◽

J. Schnermann

Keyword(s):

Blood Pressure ◽

Vascular Resistance ◽

Blood Pressure Reduction ◽

Renal Perfusion ◽

Renal Vascular Resistance ◽

Tubuloglomerular Feedback ◽

Wild Type ◽

Before And After ◽

Renal Vascular ◽

Deficient Mice

Adjustments of renal vascular resistance in response to changes in blood pressure are mediated by an interplay between the myocyte-inherent myogenic and the kidney-specific tubuloglomerular feedback (TGF) mechanisms. Using mice with deletion of the A1 adenosine receptor (A1AR) gene, we tested the prediction that the absence of TGF, previously established to result from A1AR deficiency, is associated with a reduction in the efficiency of autoregulation. In anesthetized wild-type (A1AR+/+) and A1AR-deficient mice (A1AR−/−), glomerular filtration rate (GFR) and renal blood flow (RBF) were determined before and after reducing renal perfusion pressure through a suprarenal aortic clamp. In response to a blood pressure reduction by 15.9 ± 1.34 mmHg in A1AR−/− ( n = 9) and by 14.2 ± 0.9 mmHg in A1AR+/+ mice ( n = 8; P = 0.31), GFR fell by 187.9 ± 37 μl/min and by 72.3 ± 10 μl/min in A1AR−/− and A1AR+/+ mice, respectively ( P = 0.013). Similarly, with pressure reductions of 14.8 ± 1.1 and 13.3 ± 1.5 mmHg in A1AR−/− ( n = 9) and wild-type mice ( n = 8), respectively ( P = 0.43), RBF fell by 0.17 ± 0.02 ml/min in A1AR−/− mice and by only 0.08 ± 0.02 ml/min in wild-type animals ( P = 0.0039). Autoregulatory indexes for both GFR and RBF were significantly higher in A1AR−/− compared with A1AR+/+ mice, indicating reduced regulatory responsiveness in the knockout animals. We conclude that autoregulation of renal vascular resistance is less complete in A1AR-deficient mice, an effect that is presumably related to absence of TGF regulation in these animals.

Download Full-text