Author: Tomimatsu, Masashi ; Tanaka, Shota ; Tanaka, Koki ; Chosokabe, Renya ; Okada, Yoshiaki ; Sakai, Hibiki ; Ikeda, Akari ; Kamuro, Hiroyasu ; Fujio, Yasushi ; Yamamoto, Ayaha ; Harada, Hiroki ; Obana, Masanori

A systemic inflammatory response leads to widespread organ dysfunction, such as kidney dysfunction. Plasminogen activator inhibitor-1 (PAI-1) is involved in the pathogenesis of inflammatory kidney injury; however, the regulatory mechanism of PAI-1 in injured kidneys remains unclear. PAI-1 is induced by interleukin (IL)-6 in patients with sepsis. In addition, the stabilization of IL-6 is regulated by the adenine-thymine-rich interactive domain-containing protein 5a (Arid5a). Therefore, the aim of the present study was to examine the involvement of Arid5a/IL-6/PAI-1 signaling in lipopolysaccharide (LPS)-induced inflammatory kidney injury. LPS treatment to C57BL/6J mice upregulated Pai-1 mRNA in the kidneys. Enzyme-linked immunosorbent assay (ELISA) revealed that PAI-1 expression was induced in the culture supernatants of LPS-treated human umbilical vein endothelial cells, but not in those of LPS-treated human kidney 2 (HK-2) cells, a tubular cell line. Combined with single-cell analysis, endothelial cells were found to be responsible for PAI-1 elevation in LPS-treated kidneys. Administration of TM5441, a PAI-1 inhibitor, reduced the urinary albumin/creatinine ratio, concomitant with downregulation of Il-6 and Arid5a mRNA expressions. IL-6 treatment in LPS model mice further upregulated Pai-1 mRNA expression compared with LPS alone, accompanied by renal impairment. Furthermore, the expression of Il-6 and Pai-1 mRNA was lower in Arid5a knockout mice than in wild-type mice after LPS treatment. Taken together, the vicious cycle of Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.

01 Mar 2023·Molecular Therapy - Nucleic Acids

Inducible miR-1224 silences cerebrovascular Serpine1 and restores blood flow to the stroke-affected site of the brain

Article

Author: Sen, Chandan K ; Khanna, Savita ; Sinha, Mithun ; Palakurti, Ravichand ; Biswas, Nirupam ; Roy, Sashwati ; Singh, Kanhaiya ; Gnyawali, Surya C ; Ghatak, Subhadip

The α-tocotrienol (TCT) form of natural vitamin E is more potent than the better known α-tocopherol against stroke. Angiographic studies of canine stroke have revealed beneficial cerebrovascular effects of TCT. This work seeks to understand the molecular basis of such effect. In mice, TCT supplementation improved perfusion at the stroke-affected site by inducing miR-1224. miRNA profiling of a laser-capture-microdissected stroke-affected brain site identified miR-1224 as the only vascular miR induced. Lentiviral knockdown of miR-1224 significantly blunted the otherwise beneficial effects of TCT on stroke outcomes. Studies on primary brain microvascular endothelial cells revealed direct angiogenic properties of miR-1224. In mice not treated with TCT, advance stereotaxic delivery of an miR-1224 mimic to the stroke site markedly improved stroke outcomes. Mechanistic studies identified Serpine1 as a target of miR-1224. Downregulation of Serpine1 augmented the angiogenic response of the miR-1224 mimic in the brain endothelial cells. The inhibition of Serpine1, by dietary TCT and pharmacologically, increased cerebrovascular blood flow at the stroke-affected site and protected against stroke. This work assigns Serpine1, otherwise known to be of critical significance in stroke, a cerebrovascular function that worsens stroke outcomes. miR-1224-dependent inhibition of Serpine1 can be achieved by dietary TCT as well as by the small-molecule inhibitor TM5441.

01 Dec 2021·InflammationQ2 · MEDICINE

Neuroprotective Effect of Plasminogen Activator Inhibitor-1 Antagonist in the Rat Model of Mild Traumatic Brain Injury

Q2 · MEDICINE

Article

Author: Yüksel, Meral ; Akakın, Dilek ; Akbulut, Selin ; Erzik, Can ; Kurtel, Hızır ; Eyüboğlu, İrem Peker ; Kuru Bektaşoğlu, Pınar ; Koyuncuoğlu, Türkan

Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Sprague-Dawley male rats were grouped as sham (n = 7), TBI (n = 9), and TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n = 6-7). Under anesthesia, TBI was induced by dropping a metal 300-g weight from a height of 1 m on the skull. Before and 24-h after trauma neurological examination, tail suspension, Y-maze, and novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol-, and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1β, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-β, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3, and nuclear factor-κB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Higher levels of myeloperoxidase activity in the TBI group (p < 0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p < 0.05-p < 0.01). The tail suspension test score was increased in the TBI group (p < 0.001) and decreased in all treatment groups (p < 0.05-0.001). The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p < 0.01-0.001), decreased in the treatment groups in the cortex and dentate gyrus (p < 0.05-0.001). PAI antagonists, especially TM5441, have antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

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