Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat

Yamaguchi, Naoto; Jesmin, Subrina; Zaedi, Sohel; Shimojo, Nobutake; Maeda, Seiji; Gando, Satoshi; Kôyama, Akio; Miyauchi, Takashi

doi:10.1016/j.peptides.2006.03.025

Cited by 50 publications

(44 citation statements)

References 58 publications

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“…This increase in ANG II levels by LPS was also accompanied by elevated Agt and ACE1 but diminished ACE2 expression. These results are in agreement with Yamaguchi et al (48) where they demonstrated elevated ANG II and ACE levels post-3 h endotoxemia. Interestingly, treatment of these endotoxemic animals with APC blocked the LPS-induced activation of the renal RAS components.…”

Section: Discussionsupporting

confidence: 93%

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Gupta

Rhodes

Berg³

et al. 2007

American Journal of Physiology-Renal Physiology

133

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Grinnell BW. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol 293: F245-F254, 2007. First published April 4, 2007; doi:10.1152/ajprenal.00477.2006.-Endothelial dysfunction contributes significantly to acute renal failure (ARF) during inflammatory diseases including septic shock. Previous studies have shown that activated protein C (APC) exhibits anti-inflammatory properties and modulates endothelial function. Therefore, we investigated the effect of APC on ARF in a rat model of endotoxemia. Rats subjected to lipopolysaccharide (LPS) treatment exhibited ARF as illustrated by markedly reduced peritubular capillary flow and increased serum blood urea nitrogen (BUN) levels. Using quantitative two-photon intravital microscopy, we observed that at 3 h post-LPS treatment, rat APC (0.1 mg/kg iv bolus) significantly improved peritubular capillary flow [288 Ϯ 15 m/s (LPS) vs. 734 Ϯ 59 m/s (LPSϩAPC), P ϭ 0.0009, n ϭ 6], and reduced leukocyte adhesion (P ϭ 0.003) and rolling (P ϭ 0.01) compared with the LPS-treated group. Additional experiments demonstrated that APC treatment significantly improved renal blood flow and reduced serum BUN levels compared with 24-h post-LPS treatment. Biochemical analysis revealed that APC downregulated inducible nitric oxide synthase (iNOS) mRNA levels and NO by-products in the kidney. In addition, APC modulated the renin-angiotensin system by reducing mRNA expression levels of angiotensin-converting enzyme-1 (ACE1), angiotensinogen, and increasing ACE2 mRNA levels in the kidney. Furthermore, APC significantly reduced ANG II levels in the kidney compared with the LPS-treated group. Taken together, these data suggest that APC can suppress LPS-induced ARF by modulating factors involved in vascular inflammation, including downregulation of renal iNOS and ANG II systems. Furthermore, the data suggest a potential therapeutic role for APC in the treatment of ARF.two-photon intravital microscopy; endotoxin ACUTE RENAL FAILURE (ARF) is a common complication in septic patients, with an incidence reported to be ϳ20 -50% (35, 36). The mortality rate associated with ARF in septic patients is 75% compared with 45% in patients without sepsis (38). Despite advances in supportive care with appropriate antibiotic administration and maintenance of systemic hemodynamics, coupled with the lack of proven pharmacological intervention, mortality rates for ARF patients have remained unchanged (50).During sepsis, a broad array of soluble factors are altered including the serine protease, protein C (PC). Reduction in plasma levels of PC have been shown to be prognostic for sepsis and sepsis severity (reviewed in Ref. 11). Studies have also suggested that low PC levels are predictive of early death in a rat model of polymicrobial sepsis (14). Exogenous administration of activated PC (APC) has been shown to reduce ischemia-reperfusion-induced renal injury and to attenuate microcirculatory dysfunction (16,26). These studies support...

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Section: Discussionsupporting

confidence: 93%

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Gupta

Rhodes

Berg³

et al. 2007

American Journal of Physiology-Renal Physiology

133

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“…4). This phenomenon, between the vasculature and inflammatory factors, has also been previously observed in other cells and tissues, such as the kidney, in an LPS-induced septicemia rat model (42) and in human polymorphonuclear neutrophils (36), indicating a likely widespread phenomenon in the body. This observation is consistent with the fact that three out of five cardinal signs of inflammation are dependent on vasculature, i.e., redness, heat (increased vasodilation), and swelling (increased vasopermeability) (33).…”

Section: Fig 1 Optimization Of Vegf Treatment In Mice Uterine Cervixsupporting

confidence: 70%

Vascular endothelial growth factor induces mRNA expression of pro-inflammatory factors in the uterine cervix of mice

Nguyen¹,

Minkiewicz²,

McCabe³

et al. 2012

Biomed. Res.

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Inflammation is believed to play a role in uterine cervical remodeling and infection-induced preterm labor. One of the distinct features of remodeling uterine cervix is presence of prominent vascular events, such as angiogenesis, vasodilation, and vascular permeability. Although the functional significance of these features is not yet clear, we know that in most tissue types, vascular remodeling is intricately intertwined with inflammation. Since vascular endothelial growth factor (VEGF) is the major architect of vascular remodeling, we sought to examine and elucidate the potential relationship between VEGF and inflammation in the uterine cervix of non-pregnant mice. The animals used were divided into 4 treatment groups: A) negative control (vehicle only), B) positive control (lipopolysaccharide, LPS), C) recombinant VEGF-164 protein, and D) LPS + VEGF blocker (n = 3). After the appropriate treatments, the uterine cervices were harvested and analyzed using real-time PCR and confocal fluorescence microscopy. Results showed that exogenous VEGF upregulates expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α mRNAs, whereas VEGF blocker partially diminishes the LPS-induced expression of pro-inflammatory factors compared to the positive control group. We conclude that a positive feed-forward relationship likely exists between VEGF and inflammation in the uterine cervix, thus implicating VEGF in inflammation-induced preterm labor.Inflammation is believed to play a role in uterine cervical remodeling and infection-induced preterm labor. During the course of pregnancy, the remodeling uterine cervix is, among other events, characterized by distinct vascular changes, notably, angiogenesis, vasodilation, and vascular permeability (7,(26)(27)(28). Although the functional significance of these changes during uterine cervical remodeling and at birth is, as yet, unclear, we know that vascular remodeling and inflammation are intricately intertwined (4). For instance, three of the five cardinal signs of inflammation are dependent on vascular changes, i.e., redness and heat are dependent on angiogenesis and vasodilation, whereas swelling or edema is dependent on leaky vessels or vascular permeability (33). More importantly, and of relevance to the present study, is the fact that uterine cervical remodeling and the birth process are generally considered inflammatory-like responses (25), in part, due to accumulation of immune cells and expansion of the vascular network in the uterine and uterine cervical tissues. The extent of tissue infiltration by different immune cells varies over the course of pregnancy, during and after birth (4). Data from non-human primate model studies showing successful blockade of infection-induced preterm labor using toll-like receptor 4 antagonists appear to support the role of in-

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“…These hemodynamic changes alter renal blood flow, intrarenal hemodynamics, and GFR and produce marked intrarenal vasoconstriction (10,11).…”

Section: Discussionmentioning

confidence: 99%

“…Although systemic hypotension is often present, LPS-induced ARF is characterized by marked intrarenal vasoconstriction (10,11). These hemodynamic changes alter renal blood flow, intrarenal hemodynamics and GFR.…”

Section: Introductionmentioning

confidence: 99%

Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

Cichy¹,

Rocha²,

Tristão³

et al. 2009

Braz J Med Biol Res

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Acute renal failure (ARF) is a frequent complication of Gram-negative sepsis, with a high risk of mortality. Lipopolysaccharide (LPS)-induced ARF is associated with hemodynamic changes that are strongly influenced by the overproduction of nitric oxide (NO) through the cytokine-mediated up-regulation of inducible NO synthase. LPS-induced reductions in systemic vascular resistance paradoxically culminate in renal vasoconstriction. Collagen XVIII is an important component of the extracellular matrix expressed in basement membranes. Its degradation by matrix metalloproteases, cathepsins and elastases results in the formation of endostatin, claimed to have antiangiogenic activity and to be a prominent vasorelaxing agent. We evaluated the expression of endostatin/collagen XVIII in an endotoxemic ARF model. ARF was induced in C57BL/6 mice by intraperitoneal injection of LPS (10 mg/kg) followed by sacrifice 4 and 12 h later. Kidney tissue was the source of RNA and protein and the subject of histological analysis. As early as 4 h after LPS administration, blood urea, creatinine and NO levels were significantly increased compared to control. Endostatin/collagen XVIII mRNA levels were 0.71 times lower than sham-inoculated mice 4 h after LPS inoculation, returning to normal levels 12 h after LPS inoculation. Immunohistological examination revealed that acute injury caused by LPS leads to an increase of endostatin basement membrane staining in association with the decrease of CD31 endothelial basement membrane staining. These results indicate that in the early phase of endotoxemic ARF the endostatin levels were not regulated by gene expression, but by the metabolism of collagen XVIII

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Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat

Cited by 50 publications

References 58 publications

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2

Vascular endothelial growth factor induces mRNA expression of pro-inflammatory factors in the uterine cervix of mice

Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

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