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Background The mechanism leading to the development of immunoglobulin A nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist, recently received accelerated approval in the USA for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Methods Four-week-old gddY mice were given control chow, chow containing sparsentan or drinking water containing losartan until 12 or 20 weeks old. Results Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, endothelin type A receptor and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. Conclusions The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared with AT1R antagonism alone. [ABSTRACT FROM AUTHOR]

Background: Although acute kidney injury (AKI) is associated with an increased risk of chronic kidney disease (CKD), the underlying mechanisms remain unclear. High mobility group box-1 (HMGB1), one of the ligands for the receptor for advanced glycation end products (RAGE), is elevated in patients with AKI. We recently demonstrated that the mineralocorticoid receptor (MR) is activated by the RAGE/Rac1 pathway, contributing to chronic renal damage in hypertensive mice. Therefore, this study investigated the role of the HMGB1/RAGE/MR pathway in AKI and progression to CKD., Methods: We performed a mouse model of renal ischemia-reperfusion (I/R) with or without MR antagonist (MRA). In vitro experiments were conducted using cultured endothelial cells to examine the interaction between the HMGB1/RAGE and Rac1/MR pathways., Results: In renal I/R injury mice, renal MR activation was associated with elevated serum HMGB1, renal RAGE, and activated Rac1, all of which were suppressed by MRA. Renal I/R injury led to renal dysfunction, tubulointerstitial injury, and increased expressions of inflammation and fibrosis mediators, which were ameliorated by MRA. In vitro, RAGE-aptamer or MRA inhibited HMGB1-induced Rac1/MR activation and upregulation of MCP-1 and NF-κB expressions. 7 days following I/R injury, renal I/R injury mice developed CKD, whereas MRA prevented renal injury progression and decreased mortality rate. Furthermore, in case of MRA treatment even after I/R injury, attenuated renal dysfunction compared to untreated mice was also observed., Conclusions: Our findings suggest that HMGB1 may play a crucial role in AKI and CKD development by activating the Rac1/MR pathway through interactions with RAGE., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background and Aims: Although the importance of hypertension in patients with cancer is widely recognized, little is known about the risk of developing hypertension in patients with a history of cancer., Methods and Results: This retrospective observational cohort study analysed data from the JMDC Claims Database between 2005 and 2022, including 78 162 patients with a history of cancer and 3692 654 individuals without cancer. The primary endpoint was the incidence of hypertension.During a mean follow-up period of 1208 ± 966 days, 311 197 participants developed hypertension. The incidence of hypertension was 364.6 [95% confidence interval (CI) 357.0-372.2] per 10 000 person-years among those with a history of cancer, and 247.2 (95% CI 246.3-248.1) per 10 000 person-years in those without cancer. Individuals with a history of cancer had an elevated risk of developing hypertension, according to multivariable Cox regression analyses [hazard ratio (HR) 1.17, 95% CI 1.15-1.20]. Both cancer patients requiring active antineoplastic therapy (HR 2.01, 95% CI 1.85-2.20), and those who did not require active antineoplastic therapy (HR 1.14, 95% CI 1.12-1.17) had an increased risk of hypertension. A multitude of sensitivity analyses confirmed the robustness of the relationship between cancer and incident hypertension. Patients with certain types of cancer were found to have a higher risk of developing hypertension than those without cancer, with varying risks dependent on the type of cancer., Conclusion: Our analysis of a nationwide epidemiological database revealed that individuals with a history of cancer have a higher risk of developing hypertension, and this finding applies to both cancer patients who require active antineoplastic therapy and those who do not., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)