Research progress of astragaloside IV in treating acute kidney injury.

Acute kidney injury (AKI) is one of the most common clinical critical illnesses, with decreased glomerular filtration rate, retention of nitrogen products, water and electrolyte disorders, and acid-base imbalance as the main clinical manifestations. Presently, there is no effective treatment for acute kidney injury, but the main treatment is to cure the primary disease, remove risk factors, maintain acid-base and water-electrolyte balance, and undergo kidney replacement. However, the mortality rate is still high. Investigations and studies showed that the mortality rate of patients with acute kidney injury in the ICU is 5-80% [1]. In recent years, Chinese medicine has been widely used in acute kidney injury treatment due to its complete dialectical system and rich experience. Astragalus is a commonly used medicine in traditional Chinese medicine to treat acute kidney injury. Astragaloside IV is the main active component of traditional Chinese medicine, Astragalus membranaceus. This article summarizes the relevant studies on treating acute kidney injury with astragaloside IV.

The novel methyltransferase SETD4 regulates TLR agonist-induced expression of cytokines through methylation of lysine 4 at histone 3 in macrophages.

The production of inflammatory cytokines is closely related to pathogen-associated molecular pattern (PAMP)-triggered activation of the Toll-like receptor (TLR), intracellular signal transduction pathways such as MAPK and NF-κB, and histone modifications. Histone methylation, a type of histone modifications, is mainly accomplished by a class of SET family proteins containing highly conserved SET domains. In the present study, we found that SET domain-containing protein 4 (SETD4) regulated inflammatory cytokines in response to TLR agonists. LPS stimulation led to the enhanced SETD4 expression, while the increased IL-6 and TNF-α release from LPS-stimulated RAW264.7 cells was attenuated by depletion of SETD4 using RNA interference. The results were further confirmed in BMDMs and pMφ isolated from SETD4-deficient mice where SETD4-/- macrophages treated with LPS, BLP or Poly(I:C) showed down-regulated IL-6 and TNF-α mRNA and protein levels when compared with SETD4+/+ macrophages. Moreover, the mRNA levels of all NF-κB-dependent genes including IL-1ß, IL-10, NFKBA, DUSP1, CCL2, CCL5, and CXCL10 in SETD4-/- macrophages were substantially reduced. To further clarify the regulatory mechanism(s) by which SETD4 modulates inflammatory cytokines, we examined the effect of SETD4 on the activation of MAPK and NF-κB signalling pathways, and found that knockout of SETD4 had no effect on phosphorylation of p38, ERK, JNK, p65, and IκBα. Notably, SETD4 translocated quickly from the cytosol to the nucleus upon LPS stimulation, suggesting that SETD4 may exert its regulatory function downstream of the MAPK and NF-κB pathways. To characterize this, we performed an in vitro HMTase assay to measure histone methyltransferase (HMTase) activity of SETD4. H3K4me1 and H3K4me2 levels were enhanced dramatically with the supplementation of SETD4, whereas both H3K4me1 and H3K4me2 were strongly attenuated in SETD4-/- BMDMs. Moreover, the LPS-stimulated recruitment of H3K4me1 and H3K4me2 at both TNF-α and IL-6 promoters was severely impaired in SETD4-/- BMDMs. Collectively, these results demonstrate that SETD4 positively regulates IL-6 and TNF-α expression in TLR agonist-stimulated macrophages by directly activating H3K4 methylation.