Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice

Souza, Danielle G.; Ferreira, Flávio Lopes; Fagundes, Caio T.; Amaral, Flávio Almeida; Vieira, Angélica T.; Lisboa, Rodolfo Assis; Andrade, Marcus V.; Teixeira, Mauro M.

doi:10.1016/j.ejphar.2007.05.058

Cited by 20 publications

(18 citation statements)

References 45 publications

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“…That inhibition of MMPs might be a possible option to attenuate cell damage in the intestine has to some extent been shown by Souza et al (40). Treatment of mice with dual inhibitors of the TNF-α converting enzyme and MMPs in a model of intestinal I/R injury partially inhibited the reperfusion associated lethality and tissue injury (40). Our observation that RIPC sera containing low levels of MMP-2 and MMP-9 protect intestinal epithelial cells grown in vitro from hypoxia-induced cell damage, and that addition of MMP-2 and MMP-9 to MMP-deficient culture media increases the sensitivity of CaCo-2 cells to the hypoxia-mediated damage as well implies a role of MMP-2 and MMP-9 in RIPCmediated organ protection.…”

Section: Effects Of Mmp-2 and Mmp-9 On Hypoxia-induced Cell Damagementioning

confidence: 98%

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

Zitta

Meybohm

Bein

et al. 2011

Mol Med

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Remote ischemic preconditioning (RIPC) can be induced by transient occlusion of blood flow to a limb with a blood pressure cuff and exerts multiorgan protection from ischemia/reperfusion injury. Ischemia/reperfusion injury in the intestinal tract leads to intestinal barrier dysfunction and can result in multiple organ failure. Here we used an intestinal cell line (CaCo-2) to evaluate the effects of RIPC-conditioned patient sera on hypoxia-induced cell damage in vitro and to identify serum factors that mediate RIPC effects. Patient sera (n = 10) derived before RIPC (T0), directly after RIPC (T1) and 1 h after RIPC (T2) were added to the culture medium at the onset of hypoxia until 48 h after hypoxia. Reverse transcription-polymerase chain reaction, lactate dehydrogenase (LDH) assays, caspase-3/7 assays, silver staining, gelatin zymography and Western blotting were performed. Hypoxia led to morphological signs of cell damage and increased the release of LDH in cultures containing sera T0 (P < 0.01) and T1 (P < 0.05), but not sera T2, which reduced the hypoxia-mediated LDH release compared with sera T0 (P < 0.05). Gelatin zymography revealed a significant reduction of activities of the matrixmetalloproteinase (MMP)-2 and MMP-9 in the protective sera T2 compared with the nonprotective sera T0 (MMP-2: P < 0.01; MMP-9: P < 0.05). Addition of human recombinant MMP-2 and MMP-9 to MMP-deficient culture media increased the sensitivity of CaCo-2 cells to hypoxia-induced cell damage (P < 0.05), but did not result in a reduced phosphorylation of prosurvival kinases p42/44 and protein kinase B (Akt) or increased activity of caspase-3/7. Our results suggest MMP-2 and MMP-9 as currently unknown humoral factors that may be involved in RIPC-mediated cytoprotection in the intestine.

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Section: Effects Of Mmp-2 and Mmp-9 On Hypoxia-induced Cell Damagementioning

confidence: 98%

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

Zitta

Meybohm

Bein

et al. 2011

Mol Med

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“…As PKF242-484 was shown to inhibit various matrix metalloproteinases, FN-439 (10 mg/ml, 100 l, i.p. ), a broad-range matrix metalloproteinase inhibitor that has no activity on TACE, was used as negative control (72,73). After 3 days parasitemia was measured and plasma collected for subsequent measurement of nitrite levels.…”

Section: Overexpression Of Mtnf␣ In Vivomentioning

confidence: 99%

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Forlenza

Magez²,

Scharsack³

et al. 2009

The Journal of Immunology

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Functional characterization of TNF-α in species other than mammalian vertebrates is limited, and TNF-α has been studied in a limited number of fish species, primarily in vitro using recombinant proteins. Studies on TNF-α from different fish species so far pointed to several inconsistencies, in particular with respect to some receptor-mediated activities of fish TNF-α, such as the ability to directly activate phagocytes. In the present study a comprehensive analysis of in vitro as well as in vivo biological activities of two isoforms of carp TNF-α was performed. Our results show that carp TNF-α directly primes carp phagocytes and indirectly promotes typical receptor-mediated activities such as phagocyte activation by acting via endothelial cells. Additionally, for the first time in nonmammalian vertebrate species, the lectin-like activity of fish TNF-α homologs was investigated. Our results show an evolutionary conservation of function of this receptor-independent activity of TNF-α not only in cyprinid fish, but also in perciform and salmonid fish. The role of TNF-α in vivo, during infections of carp with the blood parasite Trypanoplasma borreli, was examined using three fundamentally different but complementary approaches: (1) inhibition of TNF-α expression, (2) overexpression of TNF-α, and (3) inhibition of shedding of membrane-bound TNF-α. Our results show that, also in fish, a tight regulation of TNF-α expression is important, since depletion or excess of TNF-α can make an important difference to survival of infection. Finally, we demonstrate a crucial protective role for membrane-bound TNF-α, which has a yet unexploited function in fish.

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“…TNF484 has been successfully applied in different in vivo studies, mainly for decreasing inflammatory cytokines, such as TNF-␣ (48,50). To address whether TNF484 is able to affect klotho shedding in vivo, soluble klotho in the urine was detected via immunoblot analysis.…”

Section: Discussionmentioning

confidence: 99%

“…ADAMs are known to shed a range of proteins, so klotho-independent effects could cause the lower serum phosphate level. Until now, the effect of TNF484 treatment on phosphate homeostasis in vivo has not been investigated (48,50). Moreover, mRNA levels of the renal phosphate transporter NaPi-IIc and duodenal transporters Pit1 and Pit2 were elevated in TNF484-treated mice.…”

Section: Discussionmentioning

confidence: 99%

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Shedding of klotho by ADAMs in the kidney

Loon

Pulskens

Hagen

et al. 2015

American Journal of Physiology-Renal Physiology

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The anti-aging gene klotho plays an important role in Ca 2ϩ and phosphate homeostasis. Membrane-bound klotho is an essential coreceptor for fibroblast growth factor-23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM)10 and ADAM17. Cleavage of klotho occurs at a site directly above the plasma membrane (␣-cut) or between the KL1 and KL2 domain (␤-cut), resulting in soluble full-length klotho or KL1 and KL2 fragments, respectively. The aim of the present study was to gain insights into the mechanisms behind klotho cleavage processes in the kidney. Klotho shedding was demonstrated using a Madin-Darby canine kidney cell line stably expressing klotho and human embryonic kidney-293 cells transiently transfected with klotho. Here, we report klotho expression on both the basolateral and apical membrane, with a higher abundance of klotho at the apical membrane and in the apical media. mRNA expression of ADAM17 and klotho were enriched in mouse distal convoluted and connecting tubules. In vitro ADAM/matrix metalloproteinase inhibition by TNF484 resulted in a concentration-dependent inhibition of the ␣-cut, with a less specific effect on ␤-cut shedding. In vivo TNF484 treatment in wild-type mice did not change urinary klotho levels. However, ADAM/matrix metalloproteinase inhibition did increase renal and duodenal mRNA expression of phosphate transporters, whereas serum phosphate levels were significantly decreased. In conclusion, our data show that renal cells preferentially secrete klotho to the apical side and suggest that ADAMs are responsible for ␣-cut cleavage.klotho; a disintegrin and metalloproteinase 10; a disintegrin and metalloproteinase 17; klotho shedding; a disintegrin and metalloproteinase/matrix metalloproteinase inhibitor CA 2ϩ AND PHOSPHATE HOMEOSTASIS is a tightly regulated process involving several hormones. Klotho is emerging as a key factor in this process (5,18,51). Initially, the klotho gene was discovered as an anti-aging gene, since lack of klotho in mice resulted in early aging and a premature death (23, 26), whereas overexpression of klotho led to an increased lifespan (28).Klotho is a single-pass type 1 transmembrane protein consisting of two extracellular domains, which are the KL1 and KL2 subunits. Full-length klotho has potential enzymatic activity (30, 49), and in the body, it exists in two forms, namely, membrane-bound and soluble klotho. Membrane-bound klotho is predominantly present in the renal distal convolution, consisting of the distal convoluted tubule (DCT) and connecting tubule (CNT), parathyroid glands, and choroid plexus in the brain (26,31). A key function of membrane-bound klotho is to act as an obligate cofactor for the fibroblast growth factor (FGF) receptor, thereby enabling binding and downstream signaling of FGF23 via the ERK1/2 MAPK pathway (27, 51). In the kidney, binding of FGF23 to the receptor complex results in enhanced phosphate excretion via reduced expression of the Na ϩ -phosphate transporters NaPi-IIa and NaPiIIc (12). Moreov...

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Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice

Cited by 20 publications

References 45 publications

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

Serum from Patients Undergoing Remote Ischemic Preconditioning Protects Cultured Human Intestinal Cells from Hypoxia-Induced Damage: Involvement of Matrixmetalloproteinase-2 and -9

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

Shedding of klotho by ADAMs in the kidney

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