BACKGROUND: The fundamental role of the renin-angiotensin-aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre-clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin-angiotensin-aldosterone system blockage, along with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
METHODS: In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology.
RESULTS: The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non-nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre-clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia-reperfusion injury, proteinuria, or calcineurin inhibitor-mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions.
CONCLUSIONS: Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large-scale randomized clinical trials with long-term follow-up data.

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%-7% worldwide and 7%-10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high-risk patients. Conventional potassium-binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia-Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at-risk individuals; and (iii) correction of hyperkalaemia for at-risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region.

Background Adventitial remodeling is a pathological hallmark of hypertension that results in target organ damage. Activated adventitial fibroblasts have emerged as critical regulators in this process, but the precise mechanism remains unclear. Methods and Results Interleukin 11 (IL-11) knockout and wild-type mice were subjected to angiotensin II (Ang II) infusion to establish models of hypertension-associated vascular remodeling. IL-11 mRNA and protein were increased especially in the adventitia in response to Ang II. Compared with wild-type mice, Ang II-treated IL-11 knockout mice showed amelioration of vascular hypertrophy, adventitial fibrosis, macrophage infiltration, and inflammatory factor expression. Recombination mouse IL-11 exacerbated adventitial fibrosis in Ang II-infused wild-type mice. Interestingly, IL-11 neutralizing antibody attenuated adventitial fibrosis, macrophage infiltration, and inflammatory factor expression after Ang II infusion for 7 days. Mechanistically, in primary cultured adventitial fibroblasts, Krüppel-like factor 15 negatively regulated Ang II-induced IL-11 expression. Ang II increased extracellular signal-regulated kinases 1 and 2 activation, especially in adventitia, and caused biphasic extracellular signal-regulated kinases 1 and 2 activation in adventitial fibroblasts. A rapid and early activation increased IL-11 production through decreasing Krüppel-like factor 15 expression, which, in turn, induced the second extracellular signal-regulated kinases 1 and 2 activation, resulting in posttranscriptional profibrotic gene expression. Conclusions These results demonstrate that extracellular signal-regulated kinases 1 and 2 activation is important for Krüppel-like factor 15-mediated IL-11 expression in adventitial fibroblasts to promote adventitial remodeling in Ang II-induced hypertension. Therefore, targeting the Krüppel-like factor 15/IL-11 axis might serve as a new therapeutic strategy for vascular diseases.

BACKGROUND: Several large clinical trials have confirmed the cardioprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes. However, whether empagliflozin, as an SGLT2i, could alleviate atherosclerosis progression in non-diabetic states remain unknown.
METHODS: ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10 mg/kg/day), while another group was given normal water. At the 12th week, the whole aortas of each group were harvested. Oil Red O, HE and Movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (total cholesterol [TC], triglyceride [TG], low-density lipoprotein-c [LDL], and high-density lipoprotein-c [HDL]), systemic inflammation levels (IL-1β, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) components and sympathetic activity (norepinephrine and neuropeptide Y) indicators were measured by ELISA.
RESULTS: Empagliflozin reduced the atherosclerotic lesion burden (-8.6 %, P = 0.004) at aortic root in ApoE-/- mice. In addition, empagliflozin decreased body weight (-3.27 g, P = 0.002), lipid profiles (TC: [-15.3 mmol/L, P = 0.011]; TG: [-2.4 mmol/L, P < 0.001]; LDL: [-2.9 mmol/L, P = 0.010]), RAAS (renin [-9.3 ng/L, P = 0.047]; aldosterone [-16.7 ng/L, P < 0.001]) and sympathetic activity (norepinephrine [-8.9 ng/L, P = 0.019]; neuropeptide Y [-8.8 ng/L, P = 0.002]). However, the anti-inflammatory effect of empagliflozin was not significantly evident.
CONCLUSIONS: The early atherosclerotic lesion size was less visible in empagliflozin-treated mice. Empagliflozin could decrease lipid profiles and sympathetic activity in atherosclerosis.

Heart failure (HF) results in sustained alterations in neurohormonal signaling, including enhanced signaling through the sympathetic nervous system and renin-angiotensin-aldosterone system pathways. While enhanced sympathetic nervous system and renin-angiotensin-aldosterone system activity initially help compensate for the failing myocardium, sustained signaling through these pathways ultimately contributes to HF pathophysiology. HF remains a leading cause of mortality, with arrhythmogenic sudden cardiac death comprising a common mechanism of HF-related death. The propensity for arrhythmia development in HF occurs secondary to cardiac electrical remodeling that involves pathological regulation of ventricular ion channels, including the slow component of the delayed rectifier potassium current, that contribute to action potential duration prolongation. To elucidate a mechanistic explanation for how HF-mediated electrical remodeling predisposes to arrhythmia development, a multitude of investigations have investigated the specific regulatory effects of HF-associated stimuli, including enhanced sympathetic nervous system and renin-angiotensin-aldosterone system signaling, on the slow component of the delayed rectifier potassium current. The objective of this review is to summarize the current knowledge related to the regulation of the slow component of the delayed rectifier potassium current in response to HF-associated stimuli, including the intracellular pathways involved and the specific regulatory mechanisms.

Background Uric acid (UA) is a plasmatic antioxidant that has possible effects on blood pressure. The effects of UA on endothelial function are unclear. We hypothesize that endothelial function is not impaired unless significant UA depletion is achieved through selective xanthine oxidase inhibition with febuxostat and recombinant uricase (rasburicase). Methods and Results Microvascular hyperemia, induced by iontophoresis of acetylcholine and sodium nitroprusside, and heating-induced local hyperemia after iontophoresis of saline and a specific nitric oxide synthase inhibitor were assessed by laser Doppler imaging. Blood pressure and renin-angiotensin system markers were measured, and arterial stiffness was assessed. CRP (C-reactive protein), allantoin, chlorotyrosine/tyrosine ratio, homocitrulline/lysine ratio, myeloperoxidase activity, malondialdehyde, and interleukin-8 were used to characterize inflammation and oxidative stress. Seventeen young healthy men were enrolled in a randomized, double-blind, placebo-controlled, 3-way crossover study. The 3 compared conditions were placebo, febuxostat alone, and febuxostat together with rasburicase. The allantoin (μmol/L)/UA (μmol/L) ratio differed between sessions (P<0.0001). During the febuxostat-rasburicase session, heating-induced hyperemia became altered in the presence of nitric oxide synthase inhibition; and systolic blood pressure, angiotensin II, and myeloperoxidase activity decreased (P≤0.03 versus febuxostat). The aldosterone concentration decreased in the febuxostat-rasburicase group (P=0.01). Malondialdehyde increased when UA concentration decreased (both P<0.01 for febuxostat and febuxostat-rasburicase versus placebo). Other parameters remained unchanged. Conclusions A large and short-term decrease in UA in humans alters heat-induced endothelium-dependent microvascular vasodilation, slightly reduces systolic blood pressure through renin-angiotensin system activity reduction, and markedly reduces myeloperoxidase activity when compared with moderate UA reduction. A moderate or severe hypouricemia leads to an increase in lipid peroxidation through loss of antioxidant capacity of plasma. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03395977.