Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice.

Deposition of immune complexes in the glomerulus leads to irreversible renal damage in lupus nephritis (LN), of which podocyte malfunction arises earlier. Fasudil, the only Rho GTPases inhibitor approved in clinical settings, possesses well-established renoprotective actions; yet, no studies addressed the amelioration derived from fasudil in LN. To clarify, we investigated whether fasudil exerted renal remission in lupus-prone mice. In this study, fasudil (20 mg/kg) was intraperitoneally administered to female MRL/lpr mice for 10 weeks. We report that fasudil administration swept antibodies (anti-dsDNA) and attenuated systemic inflammatory response in MRL/lpr mice, accompanied by preserving podocyte ultrastructure and averting immune complex deposition. Mechanistically, it repressed the expression of CaMK4 in glomerulopathy by preserving nephrin and synaptopodin expression. And fasudil further blocked cytoskeletal breakage in the Rho GTPases-dependent action. Further analyses showed that beneficial actions of fasudil on the podocytes required intra-nuclear YAP activation underlying actin dynamics. In addition, in vitro assays revealed that fasudil normalized the motile imbalance by suppressing intracellular calcium enrichment, thereby contributing to the resistance of apoptosis in podocytes. Altogether, our findings suggest that the precise manners of crosstalks between cytoskeletal assembly and YAP activation underlying the upstream CaMK4/Rho GTPases signal in podocytes is a reliable target for podocytopathies treatment, and fasudil might serve as a promising therapeutic agent to compensate for the podocyte injury in LN.

Systemic lupus erythematosus and the risk of cardiovascular diseases: A two-sample Mendelian randomization study.

Background: Previous observational studies have suggested that the causal role of systemic lupus erythematosus (SLE) in the risk of cardiovascular diseases (CVDs) remained inconsistent. In this study, we aimed to investigate the causal relationship between SLE and CVDs by two-sample Mendelian randomization (MR) analysis. Methods: Genetic instruments for SLE were obtained from a public genome-wide association study (GWAS) with 4,036 patients with SLE and 6,959 controls. Summary statistical data for CVDs, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), ischemic stroke (IS), and its subtypes, were identified from other available GWAS meta-analyses. The inverse-variance weighted (IVW) method was used as the primary method to estimate the causal effect. The simple- and weighted-median method, MR-Egger method, and MR pleiotropy residual sum and outlier (MR-PRESSO) were provided as a supplement to the IVW method. Besides, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, to evaluate the robustness of the results. Results: A total of 15 single-nucleotide polymorphisms (SNPs) were identified after excluding linkage disequilibrium (LD) and potential confounding factors. According to the IVW results, our MR study indicated that genetically predicted SLE was not causally connected with the risk of CVDs [CAD: odds ratio (OR) = 1.005, 95% confidence interval (CI) = 0.986-1.024, p-value = 0.619; MI: OR = 1.002, 95% CI = 0.982-1.023, p-value = 0.854; AF: OR = 0.998, 95% CI = 0.982-1.014, p-value = 0.795; IS: OR = 1.006, 95% CI = 0.984-1.028, p-value = 0.621; cardioembolic stroke (CES): OR = 0.992, 95% CI = 0.949-1.036, p-value = 0.707; small vessel stroke (SVS): OR = 1.014, 95% CI = 0.964-1.067, p-value = 0.589; large artery stroke (LAS): OR = 1.030, 95% CI = 0.968-1.096, p-value = 0.352]. Analogical findings could be observed in supplementary MR methods. Sensitivity analyses suggested that the causal estimates were robust. Conclusion: Our two-sample MR analysis provided no evidence that genetically determined SLE was causally associated with the risk of CVDs.

Improved phenotyping procedure for evaluating resistance in rice against gall midge (Orseolia oryzae, Wood-Mason).

BACKGROUND: The rice gall midge (RGM, Orseolia oryzae, Wood-Mason), an important stem-feeding pest worldwide, has caused serious production losses over the past decades. Rice production practices indicate that the most reliable method for managing RGM is the deployment of cultivars that incorporate host resistance. However, the conventional phenotypic screening method of rice resistance to RGM suggested by the International Rice Research Institute (IRRI) has been used for approximately 30 years, and only 12 rice varieties/lines (including controls) can be evaluated in one tray. It is not suitable for high-throughput phenotyping of rice germplasm. Moreover, a suitable method to prepare samples for molecular biological studies of rice resistance against RGM is imperative with the rapid development of modern molecular techniques. RESULTS: The proper density of seedlings/RGM was determined for four seeding arrangements. A high-throughput phenotyping method (HTPM) for 60 lines/varieties infested with 36 female RGM adults in one tray, as described by method 4-3 (seeded 60 lines/varieties), was developed and verified using mutant screening. Furthermore, one RGM resistance gene flanked by markers 12RM28346 and 12RM28739 on chromosome 12 was simultaneously detected using method 2-2 (seeded 30 lines/varieties in one tray) treated with 24 RGM and analyzed using conventional and simplified grading systems. Genetic analysis of the RGM resistance gene was confirmed using a method identical to that suggested by IRRI. Finally, one bucket with 24 seedlings treated with at least five female RGM adults was efficacious and could offer adequate samples for insect development observation or molecular biological studies. CONCLUSION: A highly efficient and reliable procedure for evaluation of resistance in rice to RGM was developed and improved, and was verified through mutant screening, gene mapping, genetic analysis, and insect growth and development observations.