Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid β concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.

Aldosterone is a major mineralocorticoid steroid hormone secreted by glomerulosa cells in the adrenal cortex. It regulates a variety of physiological responses including those to oxidative stress, inflammation, fluid disruption, and abnormal blood pressure through its actions on various tissues including the kidney, heart, and the central nervous system. Aldosterone synthesis is primarily regulated by angiotensin II, K⁺ concentration, and adrenocorticotrophic hormone. Elevated serum aldosterone levels increase blood pressure largely by increasing Na⁺ re-absorption in the kidney through regulating transcription and activity of the epithelial sodium channel (ENaC). This review focuses on the signaling pathways involved in aldosterone synthesis and its effects on Na⁺ reabsorption through ENaC.

Significance Statement: If and how endothelin 1, a potent vasoconstrictor with proinflammatory and profibrotic properties, is upregulated to promote CKD is largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l exerts an antifibrotic effect by repressing the gene encoding endothelin 1 (Edn1) in the connecting tubule/collecting duct. The authors demonstrate in connecting tubule/collecting duct–specificDot1lconditional knockout mice that disruption ofDot1lfacilitates CKD development by upregulating endothelin 1, and thatDot1landEdn1double-knockout mice have a significantly attenuated CKD phenotype. Dot1l and histone deacetylase 2 mutually inhibit their association with theEdn1promoter to regulate endothelin 1 production. This study is the first to defineDot1las an epigenetic modifier of CKD, establishes a new CKD mouse model, and reveals a novel mechanism regulatingEdn1transcription.Background: The progression rate of CKD varies substantially among patients. The genetic and epigenetic contributions that modify how individual patients respond to kidney injury are largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l has an antifibrotic effect by repressingEdn1, which encodes endothelin 1 in the connecting tubule/collecting duct.Methods: To determine if deletion of theDot1lgene is a genetic and epigenetic risk factor through regulatingEdn1,we studied four groups of mice: wild-type mice, connecting tubule/collecting duct–specificDot1lconditional knockout mice (Dot1lAC),Dot1landEdn1double-knockout mice (DEAC), andEdn1connecting tubule/collecting duct–specific conditional knockout mice (Edn1AC), under three experimental conditions (streptozotocin-induced diabetes, during normal aging, and after unilateral ureteral obstruction). We used several approaches (colocalization, glutathione S-transferase pulldown, coimmunoprecipitation, yeast two-hybrid, gel shift, and chromatin immunoprecipitation assays) to identify and confirm interaction of Dot1a (the majorDot1lsplicing variant in the mouse kidney) with histone deacetylase 2 (HDAC2), as well as the function of the Dot1a-HDAC2 complex in regulatingEdn1transcription.Results: In each case,Dot1lACmice developed more pronounced kidney fibrosis and kidney malfunction compared with wild-type mice. TheseDot1lACphenotypes were ameliorated in the double-knockoutDEACmice. The interaction between Dot1a and HDAC2 prevents the Dot1a-HDAC2 complex from association with DNA, providing a counterbalancing mechanism governingEdn1transcription by modulating H3 K79 dimethylation and H3 acetylation at theEdn1promoter.Conclusions: Our study confirmsDot1lto be a genetic and epigenetic modifier of kidney fibrosis, reveals a new mechanism regulatingEdn1transcription by Dot1a and HDAC2, and reinforces endothelin 1 as a therapeutic target of kidney fibrosis.

As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in AVPR2 result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in AQP2 cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in AVPR2 and AQP2, the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.

Background: Radiotherapy (RT) causes adverse events for which there are no effective treatments. This study investigated the clinical benefits of compound Kushen injection (CKI) in managing radiation injury in patients with lung cancer. Methods: A multicenter, open-label, randomized clinical trial randomly assigned patients with lung cancer to receive either CKI (20 mL/d for at least 4 weeks) integrated with curative RT (RT + CKI group; n=130) or RT alone (control group; n=130). The primary outcome was the incidence of grade ≥2 radiation-induced lung injury (RILI) in the lungs, esophagus, or heart. Secondary outcomes included patient-reported symptoms, quality of life, objective response rate (ORR), and toxic effects. Results: During the 16-week trial, the RT + CKI group had a significantly lower incidence of grade ≥2 RT-related injury than the control group (12.3% [n=16] vs 23.1% [n=30]; P=.02). Compared with the control group, the RT + CKI group experienced a significant decrease in moderate-to-severe symptoms of fatigue, cough, and pain (P<.001 for the treatment and time interaction term); significantly less physical symptom interference (P=.01); and significantly better quality of life by the end of the trial (P<.05). No statistically significant difference in ORR was found. Adverse reactions associated with CKI were rare. Conclusions: This study demonstrated low toxicity of CKI and its effectiveness in patients with lung cancer in reducing the incidence of grade ≥2 RILI and symptom burden, improving patients' quality of life.