Renal fibrosis is a significant pathologic change associated with progressive kidney disease. Sirt6 is an NAD+-dependent deacetylase and mono-ADP ribosyltransferase known to play diverse roles in the processes attendant to aging, metabolism, and carcinogenesis. However, the role of proximal tubule-specific Sirt6 in renal fibrosis remains elusive. This study investigates the effect of proximal tubule-specific Sirt6 knockdown on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial inflammation and fibrosis. Renal fibrosis in wild type and PT-Sirt6KO (Sirt6flox/flox; Ggt1-Cre+) mice was induced by UUO surgery. After seven days, histologic examination and Western blot analysis were performed to examine extracellular matrix (ECM) protein expression. We evaluated inflammatory cytokine and cell adhesion molecule expression after ureteral obstruction. The therapeutic effect of Sirt6 activator MDL-800 on UUO-induced tubulointerstitial inflammation and fibrosis was assessed. The loss of Sirt6 in the proximal tubules aggravated UUO-induced tubular injury, ECM deposition, F4/80 positive macrophage infiltration, and proinflammatory cytokine and chemokine expression. Sirt6 activator MDL-800 mitigated UUO-induced renal tubulointerstitial inflammation and fibrosis. In an in vitro experiment, MDL-800 decreases the transforming growth factor (TGF)-β1-induced activation of myofibroblast and ECM production by regulating Sirt6-dependent β-catenin acetylation and the TGF-β1/Smad signaling pathway. In conclusion, proximal tubule Sirt6 may play an essential role in UUO-induced tubulointerstitial inflammation and fibrosis by regulating Sirt6-dependent β-catenin acetylation and ECM protein promoter transcription.

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

Renal tubulointerstitial fibrosis is characterized by sustained inflammation and excessive extracellular matrix (ECM) accumulation, leading to chronic kidney disease. Valproic acid (VPA) has anticancer activity through regulation of cell differentiation and apoptosis via inhibition of histone deacetylase (HDAC) activity and is considered a class I HDAC inhibitor. In this study, the effect of VPA on unilateral ureteral obstruction (UUO)‑induced renal fibrosis by modulation of renal inflammation and ECM gene transcription was investigated. VPA treatment increased histone H3 acetylation in both sham‑ and UUO‑operated kidneys and decreased the UUO‑induced increase in tubular injury and ECM deposition in mice. VPA also decreased myofibroblast activation and proliferation in UUO kidneys and NRK‑49F cells. Finally, it was demonstrated that the anti‑fibrotic effect of VPA was associated with regulation of ECM protein promoter enrichment at an acetylated histone H3 site. In conclusion, the findings indicate that VPA may have a beneficial effect on UUO‑induced renal fibrosis via regulation of myofibroblast activation, proliferation, and ECM protein production by chromatin remodeling and ECM protein promoter transcription.

The skin continuously serves as a biosensor of multiple exogenous stressors and integrates the resulting responses with an individual's central and peripheral endogenous response systems to perceived stress; it also acts to protect against external challenges such as wounding and infection. We have previously shown in mice that stress induces nerve growth factor- and substance P-dependent neurogenic inflammation, which includes the prominent clustering of MHC class II(+) cells. Because the contribution of dendritic cells (DCs) in response to stress is not well understood, we examined the role of DCs in neurogenic inflammation in murine skin using a well-established murine stress model. We show that sound stress increases the number of intradermal langerin(+) and CD11c(+) DCs and induces DC maturation, as indicated by the up-regulated expression of CD11c, MHC class II, and intercellular adhesion molecule-1 (ICAM-1). Blocking of ICAM-1/leukocyte function-associated antigen-1 interactions significantly abrogated the stress-induced numeric increase, maturation, and migration of dermal DCs in vivo and also reduced stress-induced keratinocyte apoptosis and endothelial cell expression of ICAM-1. In conclusion, stress exposure causes a state of immune alertness in the skin. Such adaptation processes may ensure protection from possible infections on wounding by stressors, such as attack by predators. However, present-day stressors have changed and such adaptations appear redundant and may overrun skin homeostasis by inducing immune dermatoses.

Our understanding why a woman's immune system does not reject her histoincompatible fetus is still very limited. Distinct insights into the mechanisms involved in pregnancy maintenance may help us to prevent pregnancy complications, e.g., miscarriages or pre-eclampsia. Immune integration and tolerance at the feto-maternal interface appear to be indispensable for successful pregnancy maintenance. Little is known about the cross talk between ICAM-1, expressed on epithelium, endothelium, and APC, and its ligand, LFA-1, at the feto-maternal interface. However, based on the role of ICAM-1/LFA-1 in allograft acceptance or rejection upon transplantation, adhesion molecules are likely to interfere with successful pregnancy outcome. In this study, we tested the hypothesis that ICAM-1/LFA-1 pathways may be involved in pregnancy rejection in murine models. By blocking ICAM-1/LFA-1-mediated intercellular adhesion events, we show that fetal immune acceptance is restored in challenged pregnancies (e.g., upon exposure to sound stress), and adoptive transfer of LFA-1 cells into pregnant mice induces rejection only in abortion-prone mouse models. ICAM-1/LFA-1 cross talk leads to increased recruitment of proinflammatory cells to the implantation site, promotes dendritic cell maturation in the decidua, and subsequently induces additional local Th1 polarization via mature dendritic cells. Furthermore, our observations clearly point out that mechanisms of fetal tolerance, e.g., indoleamine 2,3-dioxygenase expression, presence of CD4+CD25bright regulatory T cells, and synthesis of asymmetric Abs, are ICAM-1/LFA-1 dependent. Hence, our data shed light on a hierarchical network of immune integration at the feto-maternal interface, in which ICAM-1/LFA-1 cross talk is clearly a proximate mediator capable of disrupting successful pregnancy maintenance.