Eva Mangelsen

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E ₂ (PGE ₂ ) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE ₂ receptor type 2) and EP4 (PGE ₂ receptor type 4) in GH. Methods: We conducted in vivo studies in a transgenic zebrafish model ( Tg[fabp10a:gc-EGFP] ) suitable for analysis of glomerular filtration barrier function and a genetic rat model with GH, albuminuria, and upregulation of PGE ₂ . Similar pharmacological interventions and primary outcome analysis on albuminuria phenotype development were conducted in both model systems. Results: Stimulation of zebrafish embryos with PGE ₂ induced an albuminuria-like phenotype, thus mimicking the suggested PGE ₂ effects on glomerular filtration barrier dysfunction. Both separate and combined blockade of EP2 and EP4 reduced albuminuria phenotypes in zebrafish and rat models. A significant correlation between albuminuria and podocyte damage in electron microscopy imaging was identified in the rat model. Dual blockade of both receptors showed a pronounced synergistic suppression of albuminuria. Importantly, this occurred without changes in arterial blood pressure, glomerular filtration rate, or tissue oxygenation in magnetic resonance imaging, while RNA sequencing analysis implicated a potential role of circadian clock genes. Conclusions: Our findings confirm a role of PGE ₂ in the development of albuminuria in GH and support the renoprotective potential of combined pharmacological blockade of EP2 and EP4 receptors. These data support further translational research to explore this therapeutic option and a possible role of circadian clock genes.

β-Blockers are important drugs in the treatment of cardiovascular diseases. They are suspected of inducing various psychiatric adverse events (PAEs), particularly depression, affecting cardiovascular morbidity and mortality. We performed a systematic search for double-blind, randomized controlled trials investigating β-blockers to analyze the risk of PAEs or withdrawal of therapy due to PAEs. We extracted the frequencies of PAEs and rates of withdrawals and reviewed them to the number of exposed patients. For β-blockers versus placebo or other active treatment, we calculated odds ratios for individual PAEs and withdrawal rates. We retrieved overall 285 eligible studies encompassing 53 533 patients. The risk of bias was judged to be high in 79% of the studies. Despite being the most frequently reported PAE with a total of 1600 cases, depression did not occur more commonly during β-blockers than during placebo (odds ratio, 1.02 [95% CI, 0.83–1.25]). β-Blocker use was also not associated with withdrawal for depression (odds ratio, 0.97 [95% CI, 0.51–1.84]). Similar results were obtained for comparisons against active agents. Among other PAEs, only unusual dreams, insomnia, and sleep disorder were possibly related to β-blocker therapy. In conclusion, this analysis of large-scale data from double-blind, randomized controlled trials does not support an association between β-blocker therapy and depression. Similarly, no effect for β-blockers was found for other PAEs, with the possible exceptions of sleep-related disorders. Consequently, concerns about β-blockers’ impact on psychological health should not affect their use in clinical practice.

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman’s space. Elevated Prostaglandin E2 (PGE₂) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE₂ autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE₂, 15-keto-PGE₂, and 13,14-dihydro-15-keto-PGE₂ levels. hPC were treated with PGE₂ with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE₂ led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE₂. PTGER4 was downregulated after PGE₂ stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE₂ and 15-keto-PGE₂ levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE₂ pathway in hPC linked to concerted EP2 and EP4 signaling.