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Genome-wide association studies (GWAS) for kidney function identified hundreds of risk regions; however, the causal variants, target genes, cell types, and disease mechanisms remain poorly understood. Here, we performed transcriptome- wide association studies (TWAS), summary Mendelian randomization, and MetaXcan to identify genes whose expression mediates the genotype effect on the phenotype. Our analyses identified Dachshund homolog 1 (DACH1), a cell-fate determination factor. GWAS risk variant was associated with lower DACH1 expression in human kidney tubules. Human and mouse kidney single- cell open chromatin data (snATAC-Seq) prioritized estimated glomerular filtration rate (eGFR) GWAS variants located on an intronic regulatory region in distal convoluted tubule cells. CRISPR-Cas9-mediated gene editing confirmed the role of risk variants in regulating DACH1 expression. Mice with tubule-specific Dach1 deletion developed more severe renal fibrosis both in folic acid and diabetic kidney injury models. Mice with tubule-specific Dach1 overexpression were protected from folic acid nephropathy. Single-cell RNA sequencing, chromatin immunoprecipitation, and functional analysis indicated that DACH1 controls the expression of cell cycle and myeloid chemotactic factors, contributing to macrophage infiltration and fibrosis development. In summary, integration of GWAS, TWAS, single-cell epigenome, expression analyses, gene editing, and functional validation in different mouse kidney disease models identified DACH1 as a kidney disease risk gene., Introduction More than 1 in 10 people in the US suffers from chronic kidney disease (CKD). CKD is one of the strongest risk factors for cardiovascular death. The annual mortality [...]

Dachshund homolog 1 (DACH1), a key cell-fate determinant, regulates transcription by DNA sequence-specific binding. We identified diminished Dach1 expression in a large-scale screen for mutations that convert injury-resistant podocytes into injury-susceptible podocytes. In diabetic kidney disease (DKD) patients, podocyte DACH1 expression levels are diminished, a condition that strongly correlates with poor clinical outcomes. Global Dach1 KO mice manifest renal hypoplasia and die perinatally. Podocyte-specific Dach1 KO mice, however, maintain normal glomerular architecture at baseline, but rapidly exhibit podocyte injury after diabetes onset. Furthermore, podocyte-specific augmentation of DACH1 expression in mice protects from DKD. Combined RNA sequencing and in silico promoter analysis reveal conversely overlapping glomerular transcriptomic signatures between podocyte-specific Dach1 and Pax transactivation-domain interacting protein (Ptip) KO mice, with upregulated genes possessing higher-than-expected numbers of promoter Dach7-binding sites. PTIP, an essential component of the activating histone H3 lysine 4 trimethylation (H3K4Me3) complex, interacts with DACH1 and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increases promoter H3K4Me3. These findings reveal that in DKD, diminished DACH1 expression enhances podocyte injury vulnerability via epigenetic derepression of its target genes., Introduction Dachshund homolog 1 (DACH1) was originally identified as an essential member of the retinal determination gene network (RDGN), a fundamental signal that governs cell fate during development. That DACH1 [...]

Inflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)‐mediated nuclear factor‐κB (NF‐κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS‐IV) on anti‐inflammatory and anti‐oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS‐IV concentration‐dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro‐inflammatory cytokines as well as pro‐fibrotic factors expression, which were associated with the inhibition of NF‐κB and nuclear factor‐erythroid 2‐related factor 2 (Nrf2) signaling activation. Accordingly, both NF‐κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS‐IV to ameliorate HG‐induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3‐kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS‐IV‐induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS‐IV efficacy. Taken together, these results indicated that AS‐IV protected against HG‐induced GMCs damage by inhibiting ROS/NF‐kB‐induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up‐regulation of Nrf2‐dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation. [ABSTRACT FROM AUTHOR]

Context: Mortality from severe sepsis has been declining in recent years but remains a challenge worldwide because it remains the most frequent cause of death in ICUs. High-quality nursing care during a patient's CBP can play an important role in promoting a patient's physical condition., Objective: The study intended to explore the effects of nursing based on a humanistic care concept on continuous blood purification (CBP) treatment for patients with severe sepsis in an intensive care unit (ICU)., Design: The research team performed a prospective randomized controlled study., Setting: The study took place at Minhang Hospital at Fudan University in Shanghai, China., Participants: Participants were 80 patients with severe sepsis who had been admitted to the ICU of the hospital and who were receiving CBP between April 2021 and December 2022., Intervention: The research team randomly divided participants into two groups according to their admission sequence, with 40 participants in each group: (1) an intervention group, the humanistic care group, who received CBP under humanistic care, and (2) a control group who received CBP under routine nursing., Outcome Measures: At baseline and postintervention, the research team: (1) measured participants' negative emotions using the Self-rating Anxiety Scale (SAS) and the Self-rating Depression scale (SDS), (2) assessed participants' hope levels using the Herth Hope Index (HHI), and (3) evaluated participants' health statuses using the Acute Physiology and Chronic Health Evaluation (APACHE-II). The team also measured the complication rate and determined participants' treatment compliance., Results: Postintervention compared to the control group, the humanistic care group's: (1) SAS and SDS scores were significantly lower, with P < .001 and P < .001, respectively; (2) HHI score was significantly higher, with P < .001; (3) APACHE-II scores and complication rate were significantly lower, with P < .001 and < .001, respectively; and (4) treatment compliance was significantly higher, with P = .0186., Conclusions: Nursing based on a humanistic care concept in ICUs can effectively alleviate the negative mood of patients with severe sepsis receiving CBP, enhance their hope levels and the treatment effect, improve their health statuses and treatment compliance, and reduce the occurrence of complications.

Background: Podocyte dysfunction is associated with the progression of diabetic nephropathy (DN). Huangqi decoction (HQD), a traditional Chinese medical formula, has been used to improve diabetes-related syndrome in China. The present study was to investigate the protective effect of HQD on podocyte apoptosis and the underlying molecular mechanism., Methods: Podocyte was used to measure the efficacy of HQD on cell apoptosis, activities of NADPH oxidases, ROS generation and mitochondrial membrane potential (MMP), and the activation of Nox4/p53/Bax signaling pathway with HQD treatment were also investigated in vitro. Renal pathological morphology, renal function, podocyte apoptosis and Nox4/p53/Bax signaling pathway were investigated with STZ-induced diabetic mice in vivo., Results: HQD increased the cell proliferation and MMP level, while the ROS production and activities of NADPH oxidases were decreased. Meanwhile, Nox4/p53/Bax signaling was down-regulated. Contrarily, overexpression of Nox4 or p53 significantly abolished those efficacies of HQD. Accordingly, in vivo study showed that the progressive albuminuria, glomerulosclerosis and loss of podocytes were significantly alleviated with HQD treatment in diabetic mice, which paralleled by the marked inhibition of Nox4/p53/Bax signaling., Conclusion: Collectively, we provide further evidence that HQD had a renoprotective effect in preventing podocyte apoptosis, which was mediated at least in part by down-regulation of Nox4/p53/Bax signaling., Competing Interests: None.

Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) plays a central role in the pathogenesis of diabetes. This protein has been recognized as a potential target for diabetic therapy. In this study, we identified astragaloside IV (AS-IV) as a potent modulator of SERCA inhibiting renal injury in diabetic status. Increasing doses of AS-IV (2, 6, and 18 mg kg -1 day -1 ) were administered intragastrically to db/db mice for 8 weeks. Biochemical and histopathological approaches were conducted to evaluate the therapeutic effects of AS-IV. Cultured mouse podocytes were used to further explore the underlying mechanism in vitro . AS-IV dose-dependently increased SERCA activity and SERCA2 expression, and suppressed ER stress-mediated and mitochondria-mediated apoptosis in db/db mouse kidney. AS-IV also normalized glucose tolerance and insulin sensitivity, improved renal function, and ameliorated glomerulosclerosis and renal inflammation in db/db mice. In palmitate stimulated podocytes, AS-IV markedly improved inhibitions of SERCA activity and SERCA2 expression, restored intracellular Ca 2+ homeostasis, and attenuated podocyte apoptosis in a dose-dependent manner with a concomitant abrogation of ER stress as evidenced by the downregulation of GRP78, cleaved ATF6, phospho-IRE1α and phospho-PERK, and the inactivation of both ER stress-mediated and mitochondria-mediated apoptotic pathways. Furthermore, SERCA2b knockdown eliminated the effect of AS-IV on ER stress and ER stress-mediated apoptotic pathway, whereas its overexpression exhibited an anti-apoptotic effect. Our data obtained from in vivo and in vitro studies demonstrate that AS-IV attenuates renal injury in diabetes subsequent to inhibiting ER stress-induced podocyte apoptosis through restoring SERCA activity and SERCA2 expression.

Objective: To study the effects and mechanisms of sinensetin on proliferation and apoptosis of human AGS gastric cancer cells., Method: MTT assay was used to detect the growth inhibition rates of human AGS gastric cancer cells treated with sinsesectin in different concentrations and times. The cell cycle distribution was measured by flow cytometry. The apoptosis was examined by Annexin-FITC/PI staining and DNA fragment analysis. The apoptosis morphology was observed by inverted fluorescence microscope after Hoechst 33342 staining. The protein expressions of p21 and p53 were detected by western blot., Result: MTT assay showed that sinensetin inhibited the growth of AGS gastric cancer cells in a dose- and time-dependent manner. Sinensetin blocked AGS cells in G2/ M and increased the apoptosis rates of AGS cells in a dose-dependent manner. DNA ladder was observed in cells treated with 60 micromol x L(-1) sinensetin for 48 h. The typical apoptotic morphological changes including cell nucleus shrinkage, chromatin condensation and apoptotic bodies were observed when treated with different dose of sinensetin. Western blot showed that sinensetin increased expressions of p53 and p21 in a dose-dependent manner., Conclusion: Sinensetin could inhibit human AGS gastric cancer cells proliferation and induce cell cycle block in G2/M phase and apoptosis. The up regulation of p53 and p21 protein might be one of the mechanisms.