Rho kinase inhibition attenuates LPS-induced renal failure in mice in part by attenuation of NF-κB p65 signaling

Meyer-Schwesinger, Catherine; Dehde, Silke; Ruffer, Claudia von; Gatzemeier, Stefan; Klug, Philipp; Wenzel, Ulrich; Stahl, Rolf A.K.; Thaiss, Friedrich; Meyer, Tobias

doi:10.1152/ajprenal.90746.2008

Cited by 51 publications

(49 citation statements)

References 60 publications

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“…The first major finding of the current study was that YB-1 was upregulated in acute inflammatory processes in vivo, as demonstrated in the LPS-triggered model that has been widely used to characterize reversible renal inflammation processes in rodents (17,18) and additionally in a pyelonephritis model. We and others have previously demonstrated that YB-1 is involved in the onset of inflammation (4,(26)(27)(28).…”

Section: Discussionmentioning

confidence: 77%

“…These mice exhibit a 50% reduction in cellular YB-1 content (13,16), and gene dosage effects in comparison with wild-type (WT) littermates have not been investigated to date. To address the role of YB-1 in the inflammatory response in vivo, we induced two renal inflammatory models in WT and YB-1 +/d mice, as follows: 1) acute peritonitis following LPS injection (17,18), and 2) unilateral ureteral obstruction (UUO), in which sterile inflammation occurs secondary to mechanical renal damage and enables the study of long-term inflammation effects.…”

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confidence: 99%

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YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Hanssen

Alidousty

Djudjaj

et al. 2013

The Journal of Immunology

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In vitro studies identified Y-box–binding protein (YB)-1 as a key regulator of inflammatory mediators. In this study, we observed increased levels of secreted YB-1 in sera from sepsis patients. This led us to investigate the in vivo role of YB-1 in murine models of acute peritonitis following LPS injection, in sterile renal inflammation following unilateral ureteral obstruction, and in experimental pyelonephritis. LPS injection enhanced de novo secretion of YB-1 into the urine and the peritoneal fluid of LPS-treated mice. Furthermore, we could demonstrate a significant, transient upregulation and posttranslational modification (phosphorylation at serine 102) of YB-1 in renal and inflammatory cells. Increased renal cytoplasmic YB-1 amounts conferred enhanced expression of proinflammatory chemokines CCL2 and CCL5. Along these lines, heterozygous YB-1 knockout mice (YB-1+/d) that display 50% reduced YB-1 levels developed significantly lower responses to both LPS and sterile inflammation induced by unilateral ureteral obstruction. This included diminished immune cell numbers due to impaired migration propensities and reduced chemokine expression. YB-1+/d mice were protected from LPS-associated mortality (20% mortality on day 3 versus 80% in wild-type controls); however, immunosuppression in YB-1+/d animals resulted in 50% mortality. In conclusion, our findings identify YB-1 as a major, nonredundant mediator in both systemic and local inflammatory responses.

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Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 99%

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Hanssen

Alidousty

Djudjaj

et al. 2013

The Journal of Immunology

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“…Moreover, Rho-kinase also plays a role in mediating lysophosphatidic acid-induced NF-B activation in endothelial cells (43) and has been implicated in neuropeptide-induced NF-B activation and subsequent stimulation of IL-8 expression in colonic epithelial cells (50). In addition, Chen et al (4) showed that the Rho exchange factor mediates NF-B activation in peripheral blood monocytes, and the importance of the renal Rho-kinase/NF-B axis has been demonstrated in vivo using lipopolysaccharideinjected mice (30). These reports indicate the existence of a mechanistic linkage between the Rho/Rho-kinase pathway and the NF-B cascade.…”

Section: Discussionmentioning

confidence: 99%

Rho-kinase regulation of TNF-α-induced nuclear translocation of NF-κB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells

Matoba

Kawanami

Tsukamoto

et al. 2014

American Journal of Physiology-Renal Physiology

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The small GTPase Rho and its downstream effector, Rho-associated coiled-coil containing protein kinase (Rho-kinase), regulate a number of cellular processes, including organization of the actin cytoskeleton, cell adhesion, and migration. While pharmacological inhibitors of Rhokinase signaling are known to block renal inflammation, the molecular basis for this effect is unclear. Here, we provide evidence that proinflammatory TNF-␣ promotes mesangial expression of macrophage colony-stimulating factor (M-CSF), a key regulator for the growth and differentiation of mononuclear phagocytes, in a Rhokinase-dependent manner. Consistent with this observation, TNF-␣-mediated renal expression of M-CSF in insulin-resistant db/db mice was downregulated by Rho-kinase inhibition. Small interfering RNAfacilitated knockdown of Rho-kinase isoforms ROCK1 and ROCK2 indicated that both isoforms make comparable contributions to regulation of M-CSF expression in mesangial cells. From a mechanistic standpoint, Western blotting and EMSA showed that Rho-kinase and its downstream target p38 MAPK regulate nuclear translocation of NF-B RelA/p65 and subsequent DNA binding activity, with no significant effects on IB␣ degradation and RelA/p65 phosphorylation. Moreover, we showed that Rho-kinase-mediated cytoskeletal organization is required for the nuclear uptake of RelA/p65. Collectively, these findings identify Rho-kinase as a critical regulator of chemokine expression and macrophage proliferation.

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“…Inhibition of NF-B activation restores systemic hypotension, ameliorates septic myocardial dysfunction and vascular derangement, inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial leakage (31). Studies using a CLP model have shown that inhibition of NF-B activation significantly improves survival (22,30,33).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

Souza

Volpini

Shimizu

et al. 2012

American Journal of Physiology-Renal Physiology

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de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012 doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLPϩEPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLPϩEPOϩL-NAME). A fifth group (CLPϩEPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLPϩEPO rats presented significantly higher inulin clearance than did CLP and CLPϩEPOϩL-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLPϩEPO rats; and inulin clearance was significantly higher in CLPϩEPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLPϩEPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-␣ activation, NF-B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-B downregulation.THE MORTALITY RATES OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (5,6,26,30). Acute kidney injury (AKI) occurs in ϳ50% of patients with sepsis (5, 30). In such patients, the development of AKI is predictive of a poor outcome, and the consequent mortality has been reported to be as high as 70% (5). Despite improved strategies for supporting vital organs and resuscitating patients, the incidence and mortality rates of septic AKI remain quite high (5, 6). The prevention of kidney injury in intensive care settings continues to represent a great challenge.It has been shown that NF-B mediates the transcription of a large number of genes, the products of which are known to play important roles in septic pathophysiology (24, 31). Mice deficient in those NF-B-dependent genes are resistant to the development of septic shock and to sepsis-related mortality (31). More importantly, blockade of the NF-B pathway corr...

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Rho kinase inhibition attenuates LPS-induced renal failure in mice in part by attenuation of NF-κB p65 signaling

Cited by 51 publications

References 60 publications

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

Rho-kinase regulation of TNF-α-induced nuclear translocation of NF-κB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

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