P0143OPPOSING EFFECTS OF P38 MAPK IN PODOCYTES ON ALDOSTERONE-INDUCED GLOMERULAR INJURY IN POD-GC-A CKO MICE

Abstract Background and Aims Previously, we demonstrated that uninephrectomized aldosterone-infused, high salt-fed podocyte-specific guanylyl cyclase-A (natriuretic peptide receptor 1) conditional KO (pod-GC-A cKO) mice exhibited glomerular injury and that pharmacological inhibition of p38 MAPK ameliorates podocyte damage. However, the effects of genetic deletion of p38 MAPK in podocytes of pod-GC-A cKO mice have been unclarified. Method We generated p38 MAPK(fl/fl);Nephrin-Cre (pod-p38 MAPK cKO) mice and p38 MAPK(fl/fl);GC-A(fl/fl);Nephrin-Cre (pod-p38MAPK/GC-A DKO) mice. For induction of glomerular injury, we treated them with aldosterone and high salt at 2 months of age for 3 weeks without nephrectomy (B-ALDO). In vitro, we examined the effect of p38 MAPK inhibitor in cultured human podocytes transfected with GC-A siRNA. Results B-ALDO-treated pod-p38 MAPK/GC-A DKO mice resulted in significant elevation of serum Cr (0.29 ± 0.04 mg/dl), massive albuminuria (42,660 ± 20,200 μg/mgCr) and severe foot process effacement in addition to intracapillary fibrin thrombi which indicated endothelial damage. Vehicle-treated DKO mice, B-ALDO-treated pod-GC-A cKO mice, and B-ALDO-treated pod-p38 MAPK cKO showed normal serum Cr levels (0.14 ± 0.01, 0.18 ± 0.02, 0.20 ± 0.01 mg/dl, respectively), mild increase of albuminuria (223 ± 6.5, 1,496 ± 592, 649 ± 303 μg/mgCr, respectively) and only segmental foot process effacement. Blood pressure was not elevated in either mutant mice compared with that of B-ALDO control mice. Furthermore, glomerular mRNA expressions of MCP-1, PAI-1, and FN were upregulated and that of VEGF-A was downregulated in DKO mice. In vitro, suppression of GC-A mRNA by siRNA in combination with p38 MAPK inhibitor downregulated VEGF mRNA in human cultured podocytes. Our previous works showed that pharmacological inhibition of p38 MAPK in the whole body ameliorated podocyte damage, whereas our current result showed that genetic deletion of p38 MAPK in podocytes aggravated renal injury. In order to explain the discrepancy in these results, we added an analysis of podocyte specific GC-A fl/fl p38 fl/+ cKO mice. Pod GC-A fl/fl p38 fl/+ cKO mice exhibited considerably milder renal damage than pod GC-A fl/fl p38 fl/fl double cKO mice. Conclusion Genetic complete p38 MAPK deletion in GC-A-nul podocytes exacerbated aldosterone-induced glomerular endothelial cell injury as well as podocytes, and resulted in renal dysfunction, probably through VEGF downregulation, whereas partial p38 MAPK inhibition in podocytes ameliorated aldosterone-induced glomerular injury in pod-GC-A cKO mice. These results suggest a certain level of p38 MAPK in podocytes is necessary to protect endothelial and epithelial cells from aldosterone-induced renal injury.

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Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro and In Vivo

Anesthesiology ◽

10.1097/00000542-200606000-00023 ◽

2006 ◽

Vol 104 (6) ◽

pp. 1266-1273 ◽

Cited By ~ 45

Author(s):

Philipp Lirk ◽

Ingrid Haller ◽

Robert R. Myers ◽

Lars Klimaschewski ◽

Yi-Chuan Kau ◽

...

Keyword(s):

Sciatic Nerve ◽

P38 Mapk ◽

Local Anesthetic ◽

Apoptotic Cell ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

Background Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic. Methods Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition. Results Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580. Conclusions The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.

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IL-17A acts via p38 MAPK to increase stability of TNF-α-induced IL-8 mRNA in human ASM

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00367.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. L1283-L1290 ◽

Cited By ~ 66

Author(s):

Sheridan Henness ◽

Eveline van Thoor ◽

Qi Ge ◽

Carol L. Armour ◽

J. Margaret Hughes ◽

...

Keyword(s):

Gene Expression ◽

P38 Mapk ◽

In Vitro Study ◽

Dependent Manner ◽

Tnf Α ◽

Synthetic Function ◽

P38 Mapk Inhibitor ◽

Dependent Pathway ◽

Mapk Inhibitor

Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-α-induced IL-8 protein secretion and gene expression in a concentration- and time-dependent manner ( P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-α were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-κB, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-α-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB-203580 (−0.05763 ± 0.01964, t1/2 = 12.0 h), compared with vehicle (−0.01030 ± 0.007963, t1/2 = 67.3 h) [results are expressed as decay constant (means ± SE) and half-life ( t1/2 in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-α-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.

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In vitro activity of P38 MAPK inhibitor-loaded particles for the long term intra-articular treatment of osteoarthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.149013.26 ◽

2011 ◽

Vol 70 (Suppl 2) ◽

pp. A78-A79 ◽

Cited By ~ 1

Author(s):

J. Pradal ◽

O. Jordan ◽

C. Gabay ◽

P. A. Guerne ◽

M. C. Bagley ◽

...

Keyword(s):

P38 Mapk ◽

Vitro Activity ◽

In Vitro Activity ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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Inhibition of p38 MAPK in the brain through nasal administration of p38 inhibitor loaded in chitosan nanocapsules

Nanomedicine ◽

10.2217/nnm-2018-0496 ◽

2019 ◽

Vol 14 (18) ◽

pp. 2409-2422 ◽

Cited By ~ 1

Author(s):

Álvaro Casadomé-Perales ◽

Laura De Matteis ◽

Maria Alleva ◽

Cristina Infantes-Rodríguez ◽

Irene Palomares-Pérez ◽

...

Keyword(s):

P38 Mapk ◽

Ex Vivo ◽

Competitive Inhibitor ◽

Nasal Administration ◽

Model Of Alzheimer’S Disease ◽

P38 Mapk Inhibitor ◽

The Brain ◽

Mapk Inhibitor

Aim: To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice. Materials & methods: We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells in vitro and in ex vivo and in vivo systems, in a mouse model of Alzheimer’s disease. Results: Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity in vitro, ex vivo and in vivo. Conclusion: Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.

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SB203580, a P38 MAPK Inhibitor, Blocks in vitro Invasion by Human Gastric SNU-638 Cells

Cancer Research and Treatment ◽

10.4143/crt.2002.34.6.426 ◽

2002 ◽

Vol 34 (6) ◽

pp. 426-431

Author(s):

Ju Chae Park ◽

Hyeon Gyeung Yoo ◽

Hong Su Kim ◽

Min A Jung ◽

Mi Ha Kim ◽

...

Keyword(s):

P38 Mapk ◽

In Vitro Invasion ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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A selective p38 MAPK inhibitor alleviates neuropathology and cognitive impairment by modulating microglia function in 5XFAD mouse

10.21203/rs.2.21305/v1 ◽

2020 ◽

Author(s):

Min Sung Gee ◽

Seung Hwan Son ◽

Seung Ho Jeon ◽

Jimin Do ◽

Namkwon Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

P38 Mapk ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitor ◽

5Xfad Mice ◽

Ad Therapy ◽

Mapk Inhibitor

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibition in AD has not been ascertained yet. Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5XFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the elevation of alternatively activated M2 markers. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies. Conclusion: Taken together, our results reveal that inhibition of p38 MAPK in the brain alleviates AD pathology and represents a potential strategy for AD therapy. It also suggests that NJK14047 is a promising candidate for AD treatment. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia

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