Sang Jun Han, H. Thomas Lee. Kidney Research and Clinical Practice 2019;38:427-40. https://doi.org/10.23876/j.krcp.19.062

The role for kidney TLR9 in ischemic acute kidney injury (AKI) remains unclear. In this study, we tested the hypothesis that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular epithelial apoptosis and inflammation. To test this hypothesis, we generated mice lacking TLR9 in renal proximal tubules (TLR9^fl/fl PEPCK Cre mice). Contrasting previous studies in global TLR9 knockout mice, mice lacking renal proximal tubular TLR9 were protected against renal ischemia/reperfusion (IR) injury, with reduced renal tubular necrosis, inflammation (decreased proinflammatory cytokine synthesis and neutrophil infiltration), and apoptosis (decreased DNA fragmentation and caspase activation) when compared with wild-type (TLR9^fl/fl) mice. Consistent with this, a selective TLR9 agonist oligonucleotide 1668 exacerbated renal IR injury in TLR9^fl/fl mice but not in renal proximal tubular TLR9-null mice. Furthermore, in cultured human and mouse proximal tubule cells, TLR9-selective ligands induced NF-κB activation, proinflammatory cytokine mRNA synthesis, as well as caspase activation. We further confirm in the present study that global TLR9 deficiency had no impact on murine ischemic AKI. Taken together, our studies show that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular inflammation, apoptosis as well as necrosis, after IR via NF-κB and caspase activation. Our studies further suggest the complex nature of TLR9 activation, as renal tubular epithelial TLR9 promotes cell injury and death whereas TLR9 signaling in other cell types may promote cytoprotective effects.

Background: Renal fibrosis is characterized by the accumulation of extracellular matrix and inflammatory cells and kidney dysfunction, which is a major pathway in the progression of chronic kidney disease (CKD). Accumulating evidence indicates that oxidative stress plays a critical role in the initiation and progression of CKD via proinflammatory and profibrotic signaling pathways. Fisetin (3,3′,4′,7-tetrahydroxyflavone) has biological activities including antioxidant, anti-inflammatory, and anti-aging effects. Therefore, we evaluated the antifibrotic effects of fisetin on unilateral ureteral obstruction (UUO)-induced kidneys.Methods: C57BL/6 female mice were subjected to right UUO and intraperitoneally injected every other day with fisetin (25 mg/kg/day) or vehicle from 1 hour before surgery to 7 days after surgery. Kidney samples were analyzed for renal fibrosis (α-smooth muscle actin [α-SMA] expression, collagen deposition, and transforming growth factor [TGF] β1/SMAD3 signaling pathway), oxidative damage (4-HNE and 8-OHdG expression), inflammation (proinflammatory cytokine/chemokine, macrophage, and neutrophil infiltration), and apoptosis (TUNEL staining). Cultured human proximal tubule cells were treated with fisetin before TGF-β to confirm the TGF-β downstream pathway (SMAD2/3 phosphorylation).Result: We found that fisetin treatment protected against renal fibrosis by inhibiting the phosphorylation of SMAD3, oxidative damage, inflammation, apoptotic cell death, and accumulation of profibrotic M2 macrophages in the obstructed kidneys. In cultured human proximal tubular cells, fisetin treatment inhibited TGF-β1–induced phosphorylation of SMAD3 and SMAD2.Conclusion: Fisetin alleviates kidney fibrosis to protect against UUO-induced renal fibrosis, and could be a novel therapeutic drug for obstructive nephropathy.

Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.

Indoor microbes are readily transmitted among humans in indoor environments. Therefore, this study employed 16S rRNA gene and ITS amplicon profiling to investigate the dust-associated bacterial and fungal communities in six indoor facilities in Busan, South Korea. The collected samples were categorized into two groups: indoor multiple-use facilities (MUFs), including a public bathing facility, business office, and food court; and public transportation facilities (PTFs), including two subway stations and an airport. The bacterial diversity in the MUF samples was significantly higher than the fungal diversity (p < 0.05). However, no significant differences between bacterial and fungal diversity were observed in PTF samples (p > 0.05). Moreover, the abundances of certain microbial taxa varied, suggesting that the microbial community structure was primarily determined by the source environment. Gram-positive bacterial genera, such as Corynebacterium, Kocuria, and Staphylococcus—all of which originated in the natural environment—were relatively predominant in the MUF samples; the Aspergillus, Penicillium, and Malassezia genera, which are human commensal taxa, were relatively more predominant in the PTF samples. These results suggest that different microbial communities can be formed depending on the purpose of the indoor facility type, level of passenger traffic, and surrounding environment. The findings of this study may help researchers understand indoor microbial communities in multi-use and transportation facilities.