Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists.

BACKGROUND: Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes. RESULTS: Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non-Asians: (weighted mean difference [WMD], -0.59, 95% CI, -0.73 to -0.45, p < .01) vs (WMD, -0.29, 95% CI, -0.32 to -0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non-Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, -5.12, 95% CI, -5.84 to -4.41, p < .01) compared to non-Asians (WMD, -3.64, 95% CI, -4.38 to -2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non-Asians (p < .01). CONCLUSIONS: Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

Cardiorenal Benefits of Finerenone in Different Races and Kidney Function in Patients with Chronic Kidney Disease.

BACKGROUND: The mineralocorticoid receptor plays an important pathophysiological role in cardiorenal diseases by causing inflammation and fibrosis. Mineralocorticoid receptor antagonists (MRAs) are well known in treating cardiovascular disease and diverse nephropathies. However, the first-generation MRA (spironolactone) and the second-generation MRA (eplerenone) remain underutilized because of the risk of inducing severe adverse events. As a selective nonsteroidal MRA, finerenone is safer and more effective and improves cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). However, the effect of finerenone on cardiorenal outcomes in patients of different races and kidney function (estimated glomerular filtration rate) is unclear. SUMMARY: In this review, we summarized the impact of finerenone on patients with CKD and T2DM from randomized controlled trials. The synthesis of published data aims to address the questions pertaining to the cardiorenal benefits of finerenone among various racial groups and different levels of kidney function. KEY MESSAGE: Finerenone presents racial differences and effects associated with kidney function in CKD and T2DM patients. Due to the limited data for subgroups, it is prudent to approach the conclusion with caution.

Claudin-2 Mediates the Proximal Tubular Epithelial Cell-Fibroblast Crosstalk via Paracrine CTGF.

Purpose: Proximal tubular epithelial cell (PTEC) is vulnerable to injury in diabetic kidney disease (DKD) due to high energy expenditure. The injured PTECs-derived profibrotic factors are thought to be driving forces in tubulointerstitial fibrosis (TIF) as they activate surrounding fibroblasts. However, the mechanisms remain unclear. Methods: The diabetes with uninephrectomy (DKD) rats were used to evaluated renal histological changes and the expression of Claudin-2 by immunofluorescence staining. Then, Claudin-2 expression in PTECs were modulated and subsequently determined the proliferation and activation of fibroblasts by building a transwell co-culture system in normal glucose (NG)or high glucose (HG) condition. Results: Decreased expression of Claudin-2 in PTECs accompanied by tight junction disruption and increased interstitial fibrosis, were detected in DKD rats. In vitro, downregulated Claudin-2 in PTECs promoted proliferation and activation of fibroblasts, which coincided with elevated expression of profibrotic connective tissue growth factor (CTGF) in PTECs. Silenced CTGF inhibited the profibrotic of PTECs via Claudin-2 inhibition. Fibroblasts co-cultured with PTECs transitioned more to myofibroblasts and generated extracellular matrix (ECM) significantly in response to high glucose (HG) stimulation whereas overexpression of Claudin-2 in PTECs reversed the above results. Upregulating CTGF disrupted the beneficial anti-fibrosis effects obtained by overexpression of Claudin-2 in HG condition. Conclusion: Our study suggested that Claudin-2 in PTECs, a key mediator of paracellular cation and water transport, promotes the activation and proliferation of surrounding fibroblasts significantly via CTGF in a paracrine manner.

m6A methyltransferase METTL3 participated in sympathetic neural remodeling post-MI via the TRAF6/NF-κB pathway and ROS production.

OBJECTIVE: Sudden cardiac death caused by ventricular arrhythmias (VAs) is the main cause of high mortality in patients with myocardial infarction (MI). Sympathetic neural remodeling caused by inflammation after MI is closely associated with the occurrence of VAs. METTL3, the earliest identified m6A methyltransferase, is critical in mediating inflammatory responses. Our aim was to investigate whether the m6A methyltransferase METTL3 was involved in sympathetic remodeling post-MI and its specific mechanism. METHODS AND RESULTS: A rat MI model was established via left coronary artery ligation. The expression of METTL3, TRAF6, NOX2, and NF-κB increased at 3 days and remained elevated at 7 days after MI, as determined via Western blotting. METTL3 was primarily present in macrophages, as determined via immunofluorescence. Intramyocardial injection of lentivirus carrying METTL3-shRNA inhibited METTL3 expression in vivo. Methylated immunoprecipitation-qPCR determined the METTL3 knockdown inhibited the m6A level of TRAF6 mRNA 3'-UTR. The co-immunoprecipitation experiment proved that METTL3 combines with TRAF6. Western blotting showed that silencing METTL3 inhibited TRAF6 level, NF-κB activation, and ROS production; decreased cytokine release (TNF-α and IL-1ß); and downregulated nerve growth factor expression. Finally, METTL3 knockdown reduced sympathetic remodeling after MI, as determined via immunofluorescence assays of tyrosine hydroxylase and growth-associated protein 43. Programmed electrical stimulation, renal sympathetic nerve activity recording, and haemodynamic measurements showed that METTL3 inhibition decreased sympathetic activity and improved cardiac function. CONCLUSIONS: Downregulation of METTL3 expression attenuated the excessive sympathetic neural remodeling induced by MI, further reducing the incidence of VAs and improving cardiac function. This was partly associated with the inhibition of the TRAF6/NF-κB pathway and ROS production.

Effect of TLR4/MyD88/NF-kB axis in paraventricular nucleus on ventricular arrhythmias induced by sympathetic hyperexcitation in post-myocardial infarction rats.

Sympathetic activation after myocardial infarction (MI) leads to ventricular arrhythmias (VAs), which can result in sudden cardiac death (SCD). The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-kB) axis within the hypothalamic paraventricular nucleus (PVN), a cardiac-neural sympathetic nerve centre, plays an important role in causing VAs. An MI rat model and a PVN-TLR4 knockdown model were constructed. The levels of protein were detected by Western blotting and immunofluorescence, and localizations were visualized by multiple immunofluorescence staining. Central and peripheral sympathetic activation was visualized by immunohistochemistry for c-fos protein, renal sympathetic nerve activity (RSNA) measurement, heart rate variability (HRV) analysis and norepinephrine (NE) level detection in serum and myocardial tissue measured by ELISA. The arrhythmia scores were measured by programmed electrical stimulation (PES), and cardiac function was detected by the pressure-volume loop (P-V loop). The levels of TLR4 and MyD88 and the nuclear translocation of NF-kB within the PVN were increased after MI, while sympathetic activation and arrhythmia scores were increased and cardiac function was decreased. However, inhibition of TLR4 significantly reversed these conditions. PVN-mediated sympathetic activation via the TLR4/MyD88/NF-kB axis ultimately leads to the development of VAs after MI.

New insights into the central sympathetic hyperactivity post-myocardial infarction: Roles of METTL3-mediated m6 A methylation.

Ventricular arrhythmias (VAs) triggers by sympathetic nerve hyperactivity contribute to sudden cardiac death in myocardial infarction (MI) patients. Microglia-mediated inflammation in the paraventricular nucleus (PVN) is involved in sympathetic hyperactivity after MI. N6-methyladenosine (m6 A), the most prevalent mRNA and epigenetic modification, is critical for mediating cell inflammation. We aimed to explore whether METTL3-mediated m6 A modification is involved in microglia-mediated sympathetic hyperactivity after MI in the PVN. MI model was established by left coronary artery ligation. METTL3-mediated m6 A modification was markedly increased in the PVN at 3 days after MI, and METTL3 was primarily located in microglia by immunofluorescence. RNA-seq, MeRIP-seq, MeRIP-qPCR, immunohistochemistry, ELISA, heart rate variability measurements, renal sympathetic nerve activity recording and programmed electrical stimulation confirmed that the elevated toll-like receptor 4 (TLR4) expression by m6 A modification on TLR4 mRNA 3'-UTR region combined with activated NF-κB signalling led to the overwhelming production of pro-inflammatory cytokines IL-1ß and TNF-α in the PVN, thus inducing the sympathetic hyperactivity and increasing the incidence of VAs post-MI. Targeting METTL3 attenuated the inflammatory response and sympathetic hyperactivity and reduced the incidence of VAs post-MI.

lncRNA LOC100911717-targeting GAP43-mediated sympathetic remodeling after myocardial infarction in rats.

Objective: Sympathetic remodeling after myocardial infarction (MI) is the primary cause of ventricular arrhythmias (VAs), leading to sudden cardiac death (SCD). M1-type macrophages are closely associated with inflammation and sympathetic remodeling after MI. Long noncoding RNAs (lncRNAs) are critical for the regulation of cardiovascular disease development. Therefore, this study aimed to identify the lncRNAs involved in MI and reveal a possible regulatory mechanism. Methods and results: M0- and M1-type macrophages were selected for sequencing and screened for differentially expressed lncRNAs. The data revealed that lncRNA LOC100911717 was upregulated in M1-type macrophages but not in M0-type macrophages. In addition, the lncRNA LOC100911717 was upregulated in heart tissues after MI. Furthermore, an RNA pull-down assay revealed that lncRNA LOC100911717 could interact with growth-associated protein 43 (GAP43). Essentially, immunofluorescence assays and programmed electrical stimulation demonstrated that GAP43 expression was suppressed and VA incidence was reduced after lncRNA LOC100911717 knockdown in rat hearts using an adeno-associated virus. Conclusions: We observed a novel relationship between lncRNA LOC100911717 and GAP43. After MI, lncRNA LOC100911717 was upregulated and GAP43 expression was enhanced, thus increasing the extent of sympathetic remodeling and the frequency of VA events. Consequently, silencing lncRNA LOC100911717 could reduce sympathetic remodeling and VAs.

An all-solid-state dye-sensitized solar cell-based poly(N-alkyl-4-vinyl-pyridine iodide) electrolyte with efficiency of 5.64%.

Using poly(N-methyl-4-vinyl-pyridine iodide), N-methyl-pyridine iodide and iodine, a solid polymer electrolyte with conductivity of 6.41 mS/cm is prepared. On the basis of a solid polymer electrolyte, a conducting graphite layer, a KI block layer, and a vacuum assembling technique, we achieve an all-solid-state dye-sensitized solar cell with total photoelectric conversion efficiency of 5.64% under AM 1.5 simulated solar light (100 mW/cm2) illumination.