Edited by Xiao-Fan WangGlucocorticoids are a general class of steroids that possess renoprotective activity in glomeruli through their interaction with the glucocorticoid receptor. However, the mechanisms by which glucocorticoids ameliorate proteinuria and glomerular disease are not well understood. In this study, we demonstrated that ␣ actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in HPCs significantly reduces dexamethasone-mediated induction of GR target genes and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear translocation of GR. Synonymous mutations or protein expression losses in ACTN4 are associated with kidney diseases, including focal segmental glomerulosclerosis, characterized by proteinuria and podocyte injury. We found that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability to bind liganded GR and support GRE-mediated transcriptional activity. Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 results in reduced GR interaction and dexamethasone-mediated transactivation of a GRE reporter while still maintaining its actin-binding activity. In contrast, an ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, ANGPLT4, CCL20, and SAA1 as well as the NF-B (p65) binding sites on GR-transrepressed promoters such as IL-1␤, IL-6, and IL-8. Taken together, our data establish ACTN4 as a transcriptional co-regulator that modulates both dexamethasone-transactivated and -transrepressed genes in podocytes.

No abstract

No abstract

Acute mesenteric ischemia (AMI) is a life-threatening condition with a high mortality rate. The standard practice after making the diagnosis includes aggressive resuscitation, anticoagulation, followed by revascularization and resection of necrotic bowel. The role of empiric antibiotics in the management of AMI is not well defined in the literature. This review article aims to examine our current understanding on this matter, based on bench research and clinical studies. It is demonstrated in animal study model that the ischemia/reperfusion (I/R) injury damages intestinal epithelium, and subsequently lead to barrier dysfunction, a condition that can support bacterial translocation through a complex interplay between the intestinal epithelium, the intestinal immune system and the intestine’s endogenous bacterial population. Based on this mechanism, it is possible that the use of antibiotics may help mitigate the consequences of I/R injury, which is examined in few animal studies. In clinical practice, many guidelines support the use of prophylactic antibiotics, based on a meta-analysis of randomized control trials (RCTs) demonstrating the benefit of antibiotics in multi-organ dysfunction syndrome. However, there is no direct reference to AMI in this meta-analysis. Most clinical studies that focus on AMI and mentions the use of antibiotics are retrospective and single institution, and very few comments on the role of antibiotics in their discussions. We conclude that there is limited evidence in literature to support the use of prophylactic antibiotic in AMI to improve outcome. More clinical studies with high level of evidence and basic science research are needed to improve our understanding on this topic and ultimately help build a better clinical pathway for patients with AMI.