Reversal of Renal Fibrosis, Inflammation, and Glomerular Hypertrophy by Kallikrein Gene Delivery

Bledsoe, Grant; Shen, Bo; Yao, Yuyu; Zhang, Jenny J.; Chao, Lee; Chao, Julie

doi:10.1089/hum.2006.17.ft-203

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…Moreover, kininogens, kallikrein and pharmacologically active kinins from the kallikrein-kinin system (KKS), have been reported by numerous studies to be beneficial to cardiovascular, cerebrovascular, and renal diseases 12. Previous studies have demonstrated that KLK gene delivery reduces renal fibrosis via suppression of oxidative stress and the TGF-β/Smad signaling pathway 131415. In addition, transgenic expression of hKLK1 resists the progression of cardiac fibrosis in a rat model of diabetic cardiomyopathy 16.…”

Section: Introductionmentioning

confidence: 99%

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

et al. 2017

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Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson's trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson's trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-β 1 (TGF-β1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED.

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Section: Introductionmentioning

confidence: 99%

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

et al. 2017

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“…Using a somatic gene transfer approach, we previously demonstrated that tissue kallikrein exhibits renal protection by anti-inflammatory and anti-fibrotic actions in several animal models of renal injury (Chao et al , 1998; Murakami et al , 1998; Bledsoe et al , 2006). Furthermore, we reported that kallikrein reduced ischemia-induced cardiomyocyte apoptosis via Akt-mediated signaling pathways (Yin et al , 2005).…”

Section: Introductionmentioning

confidence: 99%

Kallikrein-Modified Mesenchymal Stem Cell Implantation Provides Enhanced Protection Against Acute Ischemic Kidney Injury by Inhibiting Apoptosis and Inflammation

et al. 2008

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Mesenchymal stem cells (MSCs) migrate to sites of tissue injury and serve as an ideal vehicle for cellular gene transfer. As tissue kallikrein has pleiotropic effects in protection against oxidative organ damage, we investigated the potential of kallikrein-modified MSCs (TK-MSCs) in healing injured kidney after acute ischemia/reperfusion (I/R). TK-MSCs secreted recombinant human kallikrein with elevated vascular endothelial growth factor levels in culture medium, and were more resistant to oxidative stress-induced apoptosis than control MSCs. Expression of human kallikrein was identified in rat glomeruli after I/R injury and systemic TK-MSC injection. Engrafted TK-MSCs exhibited advanced protection against renal injury by reducing blood urea nitrogen, serum creatinine levels, and tubular injury. Six hours after I/R, TK-MSC implantation significantly reduced renal cell apoptosis in association with decreased inducible nitric oxide synthase expression and nitric oxide levels. Forty-eight hours after I/R, TK-MSCs inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation, and expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. In addition, tissue kallikrein and kinin significantly inhibited H2O2-induced apoptosis and increased Akt phosphorylation and cell viability in cultured proximal tubular cells. These results indicate that implantation of kallikrein-modified MSCs in the kidney provides advanced benefits in protection against ischemia-induced kidney injury by suppression of apoptosis and inflammation.

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“…However, the present study did not simultaneously measure indices of renal function, which based upon the findings from the current study would be warranted in future investigations. In addition, kinins and the kallikrein system provide a critical renal protective role in the context of ischemia reperfusion injury commonly associated with cardiac surgery and cardiopulmonary bypass 35–37. The inhibition of the kinin and kallikrein pathways by aprotinin may suppress endogenous renal protective mechanisms and accentuate renal injury incurred during cardiac surgery, but this issue remains speculative and warrants further study.…”

Section: Discussionmentioning

confidence: 99%

Continuous Localized Monitoring of Plasmin Activity Identifies Differential and Regional Effects of the Serine Protease Inhibitor Aprotinin: Relevance to Antifibrinolytic Therapy

Reust

Dixon

McKinney

et al. 2011

Journal of Cardiovascular Pharmacology

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Background-Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis following cardiac surgery. However, aprotinin was empirically dosed, and while the pharmacological target was the inhibition of plasmin activity (PLact) this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic-microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact.

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Reversal of Renal Fibrosis, Inflammation, and Glomerular Hypertrophy by Kallikrein Gene Delivery

Cited by 9 publications

References 38 publications

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

Kallikrein-Modified Mesenchymal Stem Cell Implantation Provides Enhanced Protection Against Acute Ischemic Kidney Injury by Inhibiting Apoptosis and Inflammation

Continuous Localized Monitoring of Plasmin Activity Identifies Differential and Regional Effects of the Serine Protease Inhibitor Aprotinin: Relevance to Antifibrinolytic Therapy

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