Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

Liu, Yuying; Bledsoe, Grant; Hagiwara, Makato; Shen, Bo; Chao, Lee; Chao, Julie

doi:10.1152/ajprenal.00257.2012

Cited by 39 publications

(48 citation statements)

References 46 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…50 In salt-induced hypertensive rats, kallistatin therapy attenuated vascular and renal damage, and reduced oxidative stress and inflammation, 38,51 while depletion of endogenous kallistatin augmented organ injury, and accentuated oxidative stress, inflammation and fibrosis. 54 In addition, kallistatin treatment dramatically improved survival and reduced inflammation, oxidative stress, apoptosis and organ damage in mice with polymicrobial sepsis and endotoxemia. 40,52,53 Mechanistically, kallistatin inhibits vascular inflammation by interacting with the transcription factor Kruppel-like factor 4 (KLF4), leading to increased eNOS expression and NO levels in endothelial cells.…”

Section: Kallistatin Is a Unique Anti-inflammatory Agentmentioning

confidence: 99%

Protective Role of Kallistatin in Vascular and Organ Injury

2016

Self Cite

View full text Add to dashboard Cite

Kallistatin is an endogenous protein that exerts pleiotropic effects, including vasodilation and inhibition of angiogenesis, inflammation, oxidative stress, apoptosis, fibrosis, and tumor progression. Through its two functional domains – an active site and a heparin-binding site – kallistatin regulates differential signaling pathways and a wide spectrum of biological functions. Kallistatin's active site is key for inhibiting tissue kallikrein activity, and stimulating the expression of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3). Kallistatin via its heparin-binding site blocks signaling pathways mediated by growth factors and cytokines, such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), high mobility group box-1 (HMGB1), Wnt, transforming growth factor-β (TGF-β), and epidermal growth factor (EGF). Kallistatin gene or protein delivery protects against the pathogenesis of hypertension, heart and kidney damage, arthritis, sepsis, influenza virus infection, tumor growth and metastasis in animal models. Conversely, depletion of endogenous kallistatin by neutralizing antibody injection exacerbates cardiovascular and renal injury in hypertensive rats. Kallistatin levels are markedly reduced in rodents with hypertension, sepsis, streptozotocin-induced diabetes, and cardiac and renal injury. Kallistatin levels are also diminished in patients with liver disease, septic syndrome, diabetic retinopathy, severe pneumonia, inflammatory bowel disease, and obesity, prostate and colon cancer. Therefore, circulating kallistatin levels may serve as a new biomarker for human diseases. This review summarizes kallistatin's protective roles and mechanisms in vascular and organ injury, and highlights the therapeutic potential of kallistatin for multiple disease states.

show abstract

Section: Kallistatin Is a Unique Anti-inflammatory Agentmentioning

confidence: 99%

Protective Role of Kallistatin in Vascular and Organ Injury

2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that KS may function independently of its interaction with kallikrein, such as lowering blood pressure and inhibiting angiogenesis and tumor growth (14)(15)(16)(17). Recent reports showed a novel role of KS in protection against ischemia-reperfusion myocardial and salt-induced renal and cardiovascular injuries by preventing apoptosis, oxidative stress, and inflammation (18)(19)(20). Studies in inflammatory bowel disease and obesity indicated that KS was significantly decreased in patients with inflamed intestine and adiposity compared to noninflammatory controls (21,22).…”

mentioning

confidence: 99%

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Tsai

Luo

et al. 2013

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

i Group A streptococcus (GAS) infection may cause severe life-threatening diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Despite the availability of effective antimicrobial agents, there has been a worldwide increase in the incidence of invasive GAS infection. Kallistatin (KS), originally found to be a tissue kallikrein-binding protein, has recently been shown to possess anti-inflammatory properties. However, its efficacy in microbial infection has not been explored. In this study, we transiently expressed the human KS gene by hydrodynamic injection and investigated its anti-inflammatory and protective effects in mice via air pouch inoculation of GAS. The results showed that KS significantly increased the survival rate of GAS-infected mice. KS treatment reduced local skin damage and bacterial counts compared with those in mice infected with GAS and treated with a control plasmid or saline. While there was a decrease in immune cell infiltration of the local infection site, cell viability and antimicrobial factors such as reactive oxygen species actually increased after KS treatment. The efficiency of intracellular bacterial killing in neutrophils was directly enhanced by KS administration. Several inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1␤, and interleukin 6, in local infection sites were reduced by KS. In addition, KS treatment reduced vessel leakage, bacteremia, and liver damage after local infection. Therefore, our study demonstrates that KS provides protection in GAS-infected mice by enhancing bacterial clearance, as well as reducing inflammatory responses and organ damage.

show abstract

“…Local delivery of the kallistatin gene into rat heart enhances cardiac performance and atenuates inlammatory cell iniltration after acute myocardial ischemia/reperfusion (I/R) [41]. In salt-induced hypertensive rats, kallistatin therapy atenuates vascular and renal damage and reduces oxidative stress and inlammation [17,18], while depletion of endogenous kallistatin augments organ injury and accentuates oxidative stress, inlammation, and ibrosis [47].…”

Section: Kallistatin Is a Potent Anti-inlammatory Agentmentioning

confidence: 99%

“…Kallistatin administration by gene or protein delivery protects against the pathogenesis of hypertension, heart and kidney damage, arthritis, inluenza virus infection, tumor growth, and metastasis in animal models [15][16][17][18][19][41][42][43][44][45][46]. Conversely, depletion of endogenous kallistatin by neutralizing antibody injection exacerbates cardiovascular and renal injury in hypertensive rats [47]. These indings indicate that kallistatin modulates a wide spectrum of biological activities, such as blood pressure, inlammation, multiorgan injury, and cancer.…”

Section: Introductionmentioning

confidence: 97%

Kallistatin in Sepsis: Protective Actions and Potential Therapeutic Applications

Chao¹,

Li²,

Chao³

2017

Sepsis

Self Cite

View full text Add to dashboard Cite

Sepsis is a systemic inlammatory response to infection, leading to multiorgan injury and mortality. Kallistatin is an endogenous protein expressed in the liver and tissues relevant to cardiovascular function. Kallistatin levels are markedly reduced in patients with sepsis and liver disease and in lipopolysaccharide (LPS)-induced septic mice. Kallistatin administration atenuates inlammation, multiorgan damage, and lethality in septic mice with LPS treatment, group A streptococcal, or polymicrobial infection. Importantly, kallistatin treatment not only prevents but also reverses organ injury and lethality in septic mice. Kallistatin decreases sepsis-induced inlammatory responses and tissue damage by modulating diferential signaling pathways, including: (1) stimulating endothelial nitric oxide (eNOS) and sirtuin 1 (SIRT) synthesis, and NO formation; (2) increasing suppressor of cytokine signaling-3 (SOCS3) expression; (3) antagonizing tumor necrosis factor-α (TNF-α) and high mobility group box 1 (HMGB1)-mediated oxidative stress and inlammatory gene expression; and (4) displaying bactericidal efects by stimulating superoxide formation. Therefore, kallistatin's multifactorial activities provide efective protection during septic shock in animal models. As kallistatin displays no apparent cytotoxicity, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans.

show abstract

Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

Cited by 39 publications

References 46 publications

Protective Role of Kallistatin in Vascular and Organ Injury

Protective Role of Kallistatin in Vascular and Organ Injury

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Kallistatin in Sepsis: Protective Actions and Potential Therapeutic Applications

Contact Info

Product

Resources

About