Hyperactivation of p53 contributes to mitotic catastrophe in podocytes through regulation of the Wee1/CDK1/cyclin B1 axis.

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.

Humoral immune responses primed by the alteration of gut microbiota were associated with galactose-deficient IgA1 production in IgA nephropathy.

Introduction: Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. Methods: By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified. Results: The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738-0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN. Conclusion: Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.

HARMONIZE Asia: A Phase III Randomized Study to Investigate the Efficacy and Safety of Sodium Zirconium Cyclosilicate in Patients with Hyperkalemia in China.

PURPOSE: Sodium zirconium cyclosilicate (SZC) is an oral potassium (K+)-lowering therapy for adults with hyperkalemia. HARMONIZE Asia (ClinicalTrials.gov identifier: NCT03528681) evaluated the efficacy and safety of SZC in Chinese patients with hyperkalemia. METHODS: This Phase III, randomized, double-blind, placebo-controlled study recruited patients with serum K+ (sK+) ≥5.1 mmol/L at 35 sites in China. Patients received SZC 10 g three times daily (TID) for 24 or 48 hours during an open-label initial phase (OLP). Those patients achieving normokalemia (sK+ 3.5-5.0 mmol/L inclusive) entered a 28-day randomized (2:2:1) treatment phase (RTP) and received SZC 5 g, SZC 10 g, or placebo once daily. The primary endpoint was mean sK+ during RTP Days 8 to 29. Secondary endpoints included mean change in sK+ during the OLP, the proportion of patients who achieved normokalemia at the end of the OLP, the proportion that maintained normokalemia during the RTP, and time to recurrence of hyperkalemia. FINDINGS: In total, 270 patients received SZC 10 g TID during the OLP; 256 (94.8%) completed the OLP. During the OLP, mean sK+ decreased by 1.1 mmol/L from baseline (5.9 mmol/L; P < 0.001) and 87.4% of patients achieved normokalemia. During the RTP, SZC 5 g and 10 g reduced mean sK+ versus placebo in a dose-dependent manner (each P < 0.001); least-squares means (95% confidence interval [CI]) sK+ were 4.9 mmol/L (4.7, 5.0), 4.4 mmol/L (4.3, 4.6), and 5.2 mmol/L (5.1, 5.4) for SZC 5 g, 10 g, and placebo, respectively. At RTP end, the proportions of patients who maintained normokalemia were 58.8% (SZC 5 g; odds ratio vs placebo, 2.5 [95% CI: 1.1, 6.1; P = 0.035]), 76.5% (SZC 10 g; odds ratio vs placebo, 6.3 [95% CI: 2.6, 15.3; P < 0.001]), and 36.8% for placebo. Risk of recurrent hyperkalemia was reduced by 61.0% and 84.0% with SZC 5 g and SZC 10 g, respectively, versus placebo (each P < 0.001). During the RTP, the incidence of adverse events was numerically higher with SZC 5 g (50.0% of patients) and 10 g (44.0%) versus placebo (36.0%); driven primarily by peripheral edema and constipation. IMPLICATIONS: Both SZC doses demonstrated clinically relevant and statistically significant, dose-dependent efficacy in managing sK+ levels in Chinese patients with hyperkalemia, compared with placebo. SZC tolerability was broadly aligned with the known safety profile of SZC.

Genome-wide identification and expression analysis of GDP-D-mannose pyrophosphorylase and KATANIN in Corymbia citriodora.

The GDP-D-mannose pyrophosphorylase (GMP) and microtubule severing enzyme KATANIN (KTN) are crucial for wood formation. Although functional identification has been performed in Arabidopsis, few comprehensive studies have been conducted in forest trees. In this study, we discovered 8 CcGMP and 4 CcKTN genes by analyzing the whole genome sequence of Corymbia citriodora. The chromosomal location, genome synteny, phylogenetic relationship, protein domain, motif identification, gene structure, cis-acting regulatory elements, and protein-interaction of CcGMP and CcKTN were all investigated. KTN has just one pair of segmentally duplicated genes, while GMP has no duplication events. According to gene structure, two 5' UTRs were identified in CcGMP4. Furthermore, there is no protein-interaction between KTN and GMP. Based on real-time PCR, the expression of most genes showed a positive connection with DBH diameters. In addition, the expression of CcGMP4 and CcKTN4 genes were greater in different size tree, indicating that these genes are important in secondary xylem production. Overall, this findings will enhance our comprehension of the intricacy of CcGMP&CcKTN across diverse DBHs and furnish valuable insights for future functional characterization of specific genes in C. citriodora.

Population structure and genetic diversity in Eucalyptus pellita based on SNP markers.

Eucalyptus pellita has the characteristics of rapid growth and high resistance. However, there is little research on molecular breeding of E. pellita, which is essential to shortening breeding life and selecting quality varieties. Therefore, a crucial step before selective breeding can be carried out to increase the wood quality of E. pellita is identifying genetic diversity and population structure using single nucleotide polymorphism (SNP) markers. In this study, the genetic diversity of 1st generation 196 E. pellita families from 23 geographically defined was assessed using 1,677,732 SNP markers identified by whole genome resequencing. SNP annotation showed that the ratio of non-synonymous to synonymous coding mutations was 0.83. Principal component analysis (PCA), phylogenetic tree, and population structure analysis permitted the families to be categorized into three groups, one of which (G2) contains most of the Indonesian (IDN) and Papua New Guinea (PNG) families. Genetic relationship analysis showed that IDN was closely related to PNG. Genetic diversity analysis showed that He, PIC, I, and H mean values were 0.2502, 0.2027, 0.3815, and 0.2680, respectively. PCA analysis classified various provenances in QLD into two categories (G1 and G3). The genetic diversity of G3 was higher than that of G2. The results of genetic differentiation (Fst) showed that PNG region was divided into two groups (PNG1 and PNG2), the Fst (0.172) between QLD and PNG2 region was higher than QLD and PNG1, and the Fst (0.024) between IDN and PNG1 is smaller than IDN and PNG2. A Mantel test revealed a positive correlation between the genetic and geographic distance of E. pellita. This study has a certain reference value for genetic identification, germplasm preservation, and breeding of E. pellita. Also, it provides a basis for subsequent association analysis to explore excellent alleles and introduction.