Pub Date : 2026-01-22DOI: 10.1161/hypertensionaha.125.25739
Tsukasa Iwakura,Kengo Kidokoro,Rie Tatsugawa,Akira Hirano,Eriko Kajimoto,Masanobu Takasu,Masafumi Wada,Yoshihisa Wada,Hiroyuki Kadoya,Seiji Kishi,Hajime Nagasu,David Z I Cherney,Tamaki Sasaki,Naoki Kashihara
BACKGROUNDRecent studies have confirmed the protective effects of nonsteroidal MR (mineralocorticoid receptor) antagonists in diabetic kidney disease. However, the physiological mechanisms underlying their albuminuria-reducing effects remain incompletely defined. We hypothesized that inhibition of the MR could protect podocytes by limiting excessive calcium influx via TRPC (transient receptor potential canonical) 5, thereby reducing albuminuria.METHODSWe evaluated the effects of the nonsteroidal MR antagonist finerenone on albuminuria, podocyte morphology, and glomerular function in diabetic mice. Reactive oxygen species generation and single-nephron glomerular filtration rate were analyzed using in vivo imaging. Cultured podocytes were used to assess MR-TRPC5 signaling through measurements of Sgk1 (serum- and glucocorticoid-regulated kinase 1) and TRPC5 expression, intracellular calcium, and actin cytoskeletal organization.RESULTSFinerenone significantly reduced albuminuria, ameliorated podocyte morphological abnormalities, and decreased glomerular reactive oxygen species production in diabetic mice. In cultured podocytes, aldosterone increased Sgk1 and TRPC5 expression, elevated intracellular calcium, and induced actin reorganization; these changes were attenuated by finerenone and by the AC1903 (TRPC5 inhibitor). Activation of MR-TRPC signaling was associated with increased calcium influx and features of podocyte injury. In vivo imaging further indicated that finerenone was associated with lower single-nephron glomerular filtration rate, consistent with an attenuation of glomerular hyperfiltration.CONCLUSIONSFinerenone is associated with reductions in albuminuria in diabetic kidney disease, together with improvements in podocyte injury indices and glomerular hemodynamics. These benefits may be mediated in part through MR-TRPC5 signaling although additional pathways are likely to contribute.
{"title":"Finerenone Improves Albuminuria via MR-TRPC Signaling in Diabetic Kidney Disease.","authors":"Tsukasa Iwakura,Kengo Kidokoro,Rie Tatsugawa,Akira Hirano,Eriko Kajimoto,Masanobu Takasu,Masafumi Wada,Yoshihisa Wada,Hiroyuki Kadoya,Seiji Kishi,Hajime Nagasu,David Z I Cherney,Tamaki Sasaki,Naoki Kashihara","doi":"10.1161/hypertensionaha.125.25739","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.25739","url":null,"abstract":"BACKGROUNDRecent studies have confirmed the protective effects of nonsteroidal MR (mineralocorticoid receptor) antagonists in diabetic kidney disease. However, the physiological mechanisms underlying their albuminuria-reducing effects remain incompletely defined. We hypothesized that inhibition of the MR could protect podocytes by limiting excessive calcium influx via TRPC (transient receptor potential canonical) 5, thereby reducing albuminuria.METHODSWe evaluated the effects of the nonsteroidal MR antagonist finerenone on albuminuria, podocyte morphology, and glomerular function in diabetic mice. Reactive oxygen species generation and single-nephron glomerular filtration rate were analyzed using in vivo imaging. Cultured podocytes were used to assess MR-TRPC5 signaling through measurements of Sgk1 (serum- and glucocorticoid-regulated kinase 1) and TRPC5 expression, intracellular calcium, and actin cytoskeletal organization.RESULTSFinerenone significantly reduced albuminuria, ameliorated podocyte morphological abnormalities, and decreased glomerular reactive oxygen species production in diabetic mice. In cultured podocytes, aldosterone increased Sgk1 and TRPC5 expression, elevated intracellular calcium, and induced actin reorganization; these changes were attenuated by finerenone and by the AC1903 (TRPC5 inhibitor). Activation of MR-TRPC signaling was associated with increased calcium influx and features of podocyte injury. In vivo imaging further indicated that finerenone was associated with lower single-nephron glomerular filtration rate, consistent with an attenuation of glomerular hyperfiltration.CONCLUSIONSFinerenone is associated with reductions in albuminuria in diabetic kidney disease, together with improvements in podocyte injury indices and glomerular hemodynamics. These benefits may be mediated in part through MR-TRPC5 signaling although additional pathways are likely to contribute.","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"37 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1161/hypertensionaha.125.25364
Terri J Harford,Khuraijam Dhanachandra Singh,Triveni R Pardhi,Russell Desnoyer,Tarun Ravi,Zaira Palomino Jara,Ajay Zalavadia,Kate Stenson,Sathyamangla V Naga Prasad,Sadashiva S Karnik
BACKGROUNDPlasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorders. AngII (angiotensin II) infusion increases circulating 4EPS in mice, suggesting a potential mechanistic role. We hypothesized that 4EPS modulates AngII-regulated pathophysiology and disease progression by directly inhibiting AT1R (angiotensin II type 1 receptor).METHODSThis hypothesis was tested by combining AT1R pharmacology, cell signaling assays, ex vivo vascular studies, an AngII-induced aortic aneurysm growth model, and plasma proteomics analysis.RESULTSin vitro, 4EPS reduced the binding of both AngII and the antagonist candesartan to AT1R and suppressed AngII-induced calcium signaling. Ex vivo, 4EPS attenuated AngII-mediated vasoconstriction. In vivo, high-fat diet-fed ApoE-null mice coinfused with AngII and 4EPS showed significant blunting of blood pressure elevation and a marked reduction in aortic aneurysm-related mortality compared with mice infused with AngII alone. Analysis of aortic remodeling revealed increased elastin preservation and decreased thickening of the intimal and medial layers in 4EPS-treated animals. Plasma proteomics indicated alterations in actin-cytoskeletal signaling pathways consistent with reduced activation of ERK (extracellular-regulated kinase) 1/2, filamin-A, and proteins involved in vascular smooth muscle cell motility.CONCLUSIONSThese findings identify 4EPS as a benign, endogenous AT1R antagonist that diminishes AngII-mediated hemodynamic and vascular pathology. By suppressing cytoskeletal signaling associated with vascular remodeling, 4EPS provides significant protection against hypertension and aortic aneurysm progression in mice, revealing a previously unrecognized protective role for a gut microbial metabolite in modulating renin-angiotensin system activity.
{"title":"Microbial Metabolite 4EPS Inhibits AT1R to Reduce Blood Pressure and Aortic Aneurysm Outcome.","authors":"Terri J Harford,Khuraijam Dhanachandra Singh,Triveni R Pardhi,Russell Desnoyer,Tarun Ravi,Zaira Palomino Jara,Ajay Zalavadia,Kate Stenson,Sathyamangla V Naga Prasad,Sadashiva S Karnik","doi":"10.1161/hypertensionaha.125.25364","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.25364","url":null,"abstract":"BACKGROUNDPlasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorders. AngII (angiotensin II) infusion increases circulating 4EPS in mice, suggesting a potential mechanistic role. We hypothesized that 4EPS modulates AngII-regulated pathophysiology and disease progression by directly inhibiting AT1R (angiotensin II type 1 receptor).METHODSThis hypothesis was tested by combining AT1R pharmacology, cell signaling assays, ex vivo vascular studies, an AngII-induced aortic aneurysm growth model, and plasma proteomics analysis.RESULTSin vitro, 4EPS reduced the binding of both AngII and the antagonist candesartan to AT1R and suppressed AngII-induced calcium signaling. Ex vivo, 4EPS attenuated AngII-mediated vasoconstriction. In vivo, high-fat diet-fed ApoE-null mice coinfused with AngII and 4EPS showed significant blunting of blood pressure elevation and a marked reduction in aortic aneurysm-related mortality compared with mice infused with AngII alone. Analysis of aortic remodeling revealed increased elastin preservation and decreased thickening of the intimal and medial layers in 4EPS-treated animals. Plasma proteomics indicated alterations in actin-cytoskeletal signaling pathways consistent with reduced activation of ERK (extracellular-regulated kinase) 1/2, filamin-A, and proteins involved in vascular smooth muscle cell motility.CONCLUSIONSThese findings identify 4EPS as a benign, endogenous AT1R antagonist that diminishes AngII-mediated hemodynamic and vascular pathology. By suppressing cytoskeletal signaling associated with vascular remodeling, 4EPS provides significant protection against hypertension and aortic aneurysm progression in mice, revealing a previously unrecognized protective role for a gut microbial metabolite in modulating renin-angiotensin system activity.","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"28 6 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1161/hypertensionaha.125.25924
Elizabeth T Jensen,Asma M Ahmed
{"title":"Postpartum as a Window of Opportunity to Improve Women's Cardiovascular Health.","authors":"Elizabeth T Jensen,Asma M Ahmed","doi":"10.1161/hypertensionaha.125.25924","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.25924","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"22 1","pages":"e25924"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1161/hypertensionaha.125.25923
Steven J Korzeniewski
{"title":"Bridging the Biomarker Translation Gap for Hypertensive Pregnancy Disorders.","authors":"Steven J Korzeniewski","doi":"10.1161/hypertensionaha.125.25923","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.25923","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"25 1","pages":"e25923"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1161/hypertensionaha.125.24916
Clarissa Becher,Esmee J Groeneveld,Rozenn Quarck,Beau Neep,Xiaoke Pan,Robert Szulcek,Ly Tu,Christophe Guignabert,Harm Jan Bogaard,Paul B Yu,Frances de Man,Gonzalo Sanchez-Duffhues,Marie-José Goumans
BACKGROUNDPulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hypothesized that IL (interleukin)-33 signaling contributes to PAH progression by inducing EndMT and interacting with BMP9, a key modulator of inflammation and vascular remodeling.METHODSIL-33 expression was assessed in lung tissues from Sugen/hypoxia and control mice, as well as in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with PAH and healthy donors. EndMT and signaling pathways were analyzed in PAECs and microvascular endothelial cells (MVECs) exposed to IL-33, BMP9, and sST2 (soluble supression of tumorigenicity 2) using quantitative polymerase chain reaction, Western blotting, ELISA, and immunostaining. Plasma BMP9 and sST2 levels were quantified in patients with PAH.RESULTSImmunofluorescent analysis revealed elevated IL-33 expression in pulmonary endothelial cells of Sugen/hypoxia mice compared with controls, consistent with findings in PAECs from patients with PAH. BMP9 significantly upregulated sST2 expression in human PAEC and microvascular endothelial cells, inhibited IL-33 target gene expression, and effectively suppressed IL-33-induced EndMT. Notably, BMP9 demonstrated greater efficacy in preventing EndMT compared with rsST2 (recombinant soluble ST2) or ST2L-neutralizing antibodies. Circulating BMP9 and sST2 levels in the plasma of patients with PAH were positively correlated in specific patient groups stratified by sex, age, and New York Heart Association functional class, suggesting a protective role of BMP9 in modulating IL-33-induced EndMT.CONCLUSIONSBMP9 plays a protective role against IL-33-induced EndMT in PAECs by upregulating sST2 expression and neutralizing IL-33, suggesting that targeting the IL-33 signaling pathway may represent a promising therapeutic strategy to mitigate EndMT in PAH.
{"title":"BMP9 Modulates IL-33 Signaling to Mitigate EndMT in Pulmonary Arterial Hypertension.","authors":"Clarissa Becher,Esmee J Groeneveld,Rozenn Quarck,Beau Neep,Xiaoke Pan,Robert Szulcek,Ly Tu,Christophe Guignabert,Harm Jan Bogaard,Paul B Yu,Frances de Man,Gonzalo Sanchez-Duffhues,Marie-José Goumans","doi":"10.1161/hypertensionaha.125.24916","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.24916","url":null,"abstract":"BACKGROUNDPulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hypothesized that IL (interleukin)-33 signaling contributes to PAH progression by inducing EndMT and interacting with BMP9, a key modulator of inflammation and vascular remodeling.METHODSIL-33 expression was assessed in lung tissues from Sugen/hypoxia and control mice, as well as in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with PAH and healthy donors. EndMT and signaling pathways were analyzed in PAECs and microvascular endothelial cells (MVECs) exposed to IL-33, BMP9, and sST2 (soluble supression of tumorigenicity 2) using quantitative polymerase chain reaction, Western blotting, ELISA, and immunostaining. Plasma BMP9 and sST2 levels were quantified in patients with PAH.RESULTSImmunofluorescent analysis revealed elevated IL-33 expression in pulmonary endothelial cells of Sugen/hypoxia mice compared with controls, consistent with findings in PAECs from patients with PAH. BMP9 significantly upregulated sST2 expression in human PAEC and microvascular endothelial cells, inhibited IL-33 target gene expression, and effectively suppressed IL-33-induced EndMT. Notably, BMP9 demonstrated greater efficacy in preventing EndMT compared with rsST2 (recombinant soluble ST2) or ST2L-neutralizing antibodies. Circulating BMP9 and sST2 levels in the plasma of patients with PAH were positively correlated in specific patient groups stratified by sex, age, and New York Heart Association functional class, suggesting a protective role of BMP9 in modulating IL-33-induced EndMT.CONCLUSIONSBMP9 plays a protective role against IL-33-induced EndMT in PAECs by upregulating sST2 expression and neutralizing IL-33, suggesting that targeting the IL-33 signaling pathway may represent a promising therapeutic strategy to mitigate EndMT in PAH.","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"24 1","pages":"e24916"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Accuracy of Visually Estimated Home Blood Pressure: Result From the Estimating Yield of Eyeballed BP Study.","authors":"Jesslin Abraham,Yinying Wei,Bau Tran,Stephanie Brinker,Angela Price,Zaiba Jetpuri,Salahuddin Kazi,John M Giacona,Wanpen Vongpatanasin","doi":"10.1161/hypertensionaha.125.26412","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.26412","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"7 1","pages":"e26412"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1161/hypertensionaha.125.25906
Lance N Benson,Kelly A Hyndman,David M Pollock,Jennifer S Pollock
{"title":"Time of Day Drives Angiotensin II-Dependent Hypertension.","authors":"Lance N Benson,Kelly A Hyndman,David M Pollock,Jennifer S Pollock","doi":"10.1161/hypertensionaha.125.25906","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.25906","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"277 1","pages":"e25906"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1161/hypertensionaha.125.26437
Samuel S Gidding,Raymond R Townsend
{"title":"One Way Children With Elevated Blood Pressure Become Adults With Hypertension.","authors":"Samuel S Gidding,Raymond R Townsend","doi":"10.1161/hypertensionaha.125.26437","DOIUrl":"https://doi.org/10.1161/hypertensionaha.125.26437","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":"31 1","pages":"e26437"},"PeriodicalIF":8.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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