Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPK

Polzer, K; Soleiman, Afschin; Baum, Wolfgang; Axmann, Roland; Distler, Jörg H W; Redlich, Kurt; Kilian, Anita; Krönke, Gerhard; Schett, Georg; Zwerina, Jochen

doi:10.1136/ard.2007.077263

Cited by 17 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach was based on the fact that abnormally activated p38 MAPK signaling in podocytes was observed in human disease, as well as in several animal models of NS (11,31,46,52,(57)(58)(59)68). By protecting PAN-injured cultured podocytes with the p38 MAPK inhibitor SB203580, we were able to confirm this concept.…”

Section: Discussionsupporting

confidence: 57%

See 1 more Smart Citation

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

While mitogen-activated protein kinase (MAPK) activation has been implicated in the pathogenesis of various glomerular diseases, including nephrotic syndrome (NS), its specific role in podocyte injury is not known. We hypothesized that MK-2, a downstream substrate of p38 MAPK, mediates the adverse effects of this pathway and that inhibition of MK-2 would protect podocytes from NS-related injury. Using cultured podocytes, we analyzed 1) the roles of MK-2 and p38 MAPK in puromycin aminonucleoside (PAN)-induced podocyte injury; 2) the ability of specific MK-2 and p38 MAPK inhibitors to protect podocytes against injury; 3) the role of serum albumin, known to induce podocyte injury, in activating p38 MAPK/MK-2 signaling; and 4) the role of p38 MAPK/MK-2 signaling in the expression of Cox-2, an enzyme associated with podocyte injury. Treatment with protein kinase inhibitors specific for both MK-2 (C23, a pyrrolopyridine-type compound) or p38 MAPK (SB203580) reduced PAN-induced podocyte injury and actin cytoskeletal disruption. Both inhibitors reduced baseline podocyte p38 MAPK/MK-2 signaling, as measured by the degree of phosphorylation of HSPB1, a downstream substrate of MK-2, but exhibited disparate effects on upstream signaling. Serum albumin activated p38 MAPK/MK-2 signaling and induced Cox-2 expression, and these responses were blocked by both inhibitors. Given the critical importance of podocyte injury to both NS and other progressive glomerular diseases, these data suggest an important role for p38 MAPK/MK-2 signaling in podocyte injury and identify MK-2 inhibition as a promising potential therapeutic strategy to protect podocytes in various glomerular diseases.

show abstract

Section: Discussionsupporting

confidence: 57%

“…In human crescentic glomerulonephritis, as well as experimental animal models of glomerulonephritis, activated p38 MAPK signaling has been observed in podocytes (46,52,(57)(58)(59). Similarly, increased phosphorylation (activation) of p38 MAPK has been reported in various human glomerulopathies as well as in experimental rodent nephrosis models (31).…”

mentioning

confidence: 99%

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Pengal

Guess

Agrawal

et al. 2011

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…The p38a and p38b isoforms play predominant roles in immune cell activation, so the majority of p38 MAPK inhibitors developed for the treatment of inflammation have been targeted against these isoforms in order to avoid unwanted physiological effects through p38c and p38d inhibition. It has been shown in glomerulonephritis that p38a is the most highly expressed isoform in infiltrating leukocytes in the kidney [17], but there was also evidence of p38b and p38c isoform expression in structural cell types. The expression levels of p38 MAPK isoforms in the lungs of COPD patients have not been quantitatively studied; this would identify the isoforms relevant to the pathophysiology of COPD.…”

Section: Introductionmentioning

confidence: 98%

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

et al. 2012

View full text Add to dashboard Cite

The p38 mitogen-activated protein kinase (MAPK) pathway is upregulated in chronic obstructive pulmonary disease (COPD). To date, dual labelling to identify cell-type-specific presence of phosphorylated (phospho-)p38 MAPK has not been carried out.Phospho-p38 MAPK was quantified in a variety of cell types in the lung tissue of 20 COPD patients, 12 smokers and 12 nonsmokers using immunohistochemistry. Paired blood and sputum neutrophils (from seven subjects with COPD), and CD8 and epithelial cells (from three subjects with COPD) were cultured with a p38 MAPK inhibitor. Supernatant tumour necrosis factor-a and CXCL8 levels were analysed by ELISA. Sputum and blood neutrophil cytospins were analysed for phospho-p38 MAPK.Phospho-p38 MAPK was increased in bronchial epithelial cells, macrophages and CD20+ and CD8+ lymphocytes in COPD lungs. Sputum and lung tissue neutrophils were devoid of phospho-p38 in all patient groups. The p38 MAPK inhibitor SB100 attenuated pro-inflammatory mediator release in COPD lung CD8 cells and airway epithelia, but there was no effect on COPD sputum neutrophils.Our data indicate cell-specific anti-inflammatory effects of p38 MAPK inhibition in the lung. @ERSpublications p38 MAPK inhibition causes cell-specific anti-inflammatory effects in the lung

show abstract

mentioning

confidence: 99%

“…A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling pathways could not be excluded. 18 Recent studies suggest that the mammalian target of rapamycin complex 1 (mTORC1) cascade has a regulatory role in the signaling pathways that control cellular growth and proliferation. 19,20 Signaling through the mTORC1 pathway is activated by growth factors and nutrients, of which branched-chain amino acids (BCAA) are potent intracellular stimulators.…”

mentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

show abstract

Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPK

Cited by 17 publications

References 19 publications

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Inhibition of the protein kinase MK-2 protects podocytes from nephrotic syndrome-related injury

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Contact Info

Product

Resources

About