Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-β, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin–angiotensin–aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima–media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current treatments for DKD do not halt renal injury progression, highlighting an urgent need for therapies targeting key disease mechanisms. Our previous studies demonstrated that activating the Sigma-1 receptor (S1R) with fluvoxamine (FLU) protects against acute kidney injury by inhibiting inflammation and ameliorating the effect of hypoxia. Based on these, we hypothesized that FLU might exert a similar protective effect in DKD. Diabetes was induced in male Wistar rats using streptozotocin, followed by a seven-week FLU treatment. Metabolic and renal parameters were assessed along with a histological analysis of glomerular damage and fibrosis. The effects of FLU on inflammation, hypoxia, and fibrosis were tested in human proximal tubular cells and normal rat kidney fibroblasts. FLU improved renal function and reduced glomerular damage and tubulointerstitial fibrosis. It also mitigated inflammation by reducing TLR4, IL6, and NFKB1 expressions and moderated the cellular response to tubular hypoxia. Additionally, FLU suppressed TGF-β1-induced fibrotic processes and fibroblast transformation. These findings suggest that S1R activation can slow DKD progression and protect renal function by modulating critical inflammatory, hypoxic, and fibrotic pathways; therefore, it might serve as a promising novel drug target for preventing DKD.

Introduction and aims: Idiopathic pulmonary fibrosis is associated with a median survival of just 2-3 years after diagnosis. Current therapies ameliorate pulmonary functional decrement, but do not inhibit the progression of fibrosis or reduce mortality. Thus, effective anti-fibrotic therapies are desperately needed. Based on our previous results in other organs, we aimed to investigate whether Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) can ameliorate pulmonary fibrosis. Methods: Fibrotic processes were induced with TGF-β or PDGF in A549 lung epithelial cells and primary fibroblasts isolated from the lungs of wt and S1R-/- mice. Cells were treated with FLU. Pulmonary fibrosis was induced in wild-type and S1R-/- mice by oropharyngeal bleomycin (BLM) administration. Mice were treated daily with FLU and sacrificed after 21 days. Results: FLU mitigated α-SMA production and F-actin formation in both A549 cells and primary lung fibroblasts after pro-fibrotic factor induction. The effect of FLU was not obeserved in fibroblasts isolated from S1R-/- mice. In mice, after 21 days pro-fibrotic factor Tgfb expression was unaltered, while Ctgf expression increased in the BLM group, but not in the wt BLM+FLU group. Elevated expressions of ECM components collagen I, collagen III and fibronectin were reduced to control levels in wt BLM+FLU mice. Evaluation of Masson9s trichrome-stained sections underlined the massive anti-fibrotic effect of FLU. In vivo MicroCT showed more preserved aerated tissue area in wt BLM+FLU vs. wt BLM and S1R-/- BLM+FLU. Conclusions: Based on our preclinical data S1R may be a novel, effective drug target in the treatment of pulmonary fibrosis.

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease. Maintaining organ viability between donation and transplantation, as well as minimizing ischemic injury, are critically important for long-term graft function and survival. Moreover, the increasing shortage of transplantable organs is a considerable problem; thus, optimizing the condition of grafts is a pivotal task. Here, rodent models of kidney transplantation and cold storage were used to demonstrate that supplementation of a preservation solution with Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) reduces cold and warm ischemic injury. Post-transplant kidney function was improved, histological injury was mitigated, and mRNA expression of two tubular injury markers-kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin-was robustly reduced. In addition, renal inflammation was diminished, as shown by reduced leukocyte infiltration and pro-inflammatory cytokine expression. In the cold ischemia model, FLU ameliorated structural injury profoundly after 2 h as well as 24 h. The reduced number of TUNEL-positive and Caspase 3-positive cells suggests the anti-apoptotic effect of FLU. None of these beneficial effects of FLU were observed in S1R(-/-) mice. Of note, organ damage in FLU-treated kidneys after 24 h of cold storage was similar to just 2 h without FLU. These results indicate that S1R agonists can prolong storage time and have great potential in improving organ preservation and in alleviating the problem of organ shortages.

Perinatal asphyxia (PA) is associated with more than half a million mature newborn deaths yearly. It may lead to severe complications including hypoxic encephalopathy, renal- hepatic- and cardiovascular injury, as well as respiratory distress, Basic research and clinical trials mainly focus on mitigating central nervous system damage by selective head or whole body cooling, which is currently the only routinely used treatment in clinical practice. However, the extent of PA-associated multi-organ damage is not clarified yet and effective therapies are lacking. Our aim was to investigate the acute renal, hepatic and cardiac impairment following PA and to identify pathways involved in the pathomechanism. In addition, we aimed to explore long-term effects of PA on permanent organ damage and susceptibility to ischemia/-reperfusion injury in adulthood. Postnatal 7 day-old male Wistar rat pups (n=5-10/group) were randomly grouped as follows: (i) Baseline; (ii) Control; (iii) PA. The PA group was separated from the dam and received asphyxic gas mixture (4% O2; 20% CO2 in N2) for 15 minutes, while Control animals received normal air following separation. Serum and tissue samples were collected after 4 (T4) or 24 (T24) hours. In a second experiment 35 min bilateral renal ischemic insult was performed on control and PA rats aged 6 months (n=6-7/group). Serum and tissue samples were collected 24 (T24 IR) hours after reperfusion (Figure 1). Serum levels of electrolytes, kidney and liver functional parameters, and myocardial ischemic protein Troponin I were determined. Highly selective and sensitive tubular injury markers (Kim1, Ngal) were measured. Expressions of hypoxic (Hif1a, Hif2a) inflammatory (Il1α, Il1β, Il6, Tnfα, Mcp1, Tlr2), apoptotic (Bax, Bcl-2) and angiogenic genes (Vegf, Epo) and heat shock proteins (Hsp27, Hsp72) were investigated. Periodic-Acid Schiff stained kidney sections and Hematoxylin & Eosin stained liver sections were evaluated for structural injury. Blood urea nitrogen (BUN) and serum GPT were elevated at T4 following PA. Kim1, Ngal and heat shock protein expressions were increased, inflammatory and angiogenic pathways were activated in the kidney after PA. In the liver hypoxic and apoptotic pathways were activated at T24 in controls and after asphyxia, but not in the Baseline group. Vacuolisation, cytoplasmic degradation, and the onset of necrosis were observed in the liver following PA. Serum Troponin I was elevated indicating myocardial damage, moreover inflammatory cytokines and heat shock proteins increased in the heart. In adult PA rats BUN levels were elevated, suggesting a long-term detrimental effect of PA on renal function. In addition, adult PA rats were more susceptible to renal ischemic insult, confirmed by higher serum creatinine and GPT levels, as well as increased expression of tubular injury, hypoxic and inflammatory markers compared to Control rats subjected to ischemia. Acute renal, hepatic and myocardial impairment was observed after PA. These results may justify the need for clinical follow-up and novel treatment strategies for possible multi-organ damage. The molecular pathways described here are potential targets for therapeutic intervention. In addition, birth asphyxia may increase sensitivity to renal injury in adulthood, which may be worth considering in clinical situations with potential renal impairment.

The properties of the liquids change at the interaction with electrical discharges. This offers the so activated liquids a variety of possible applications in the biomedical field. The paper investigates the bacterial inhibition effects of plasma activated water on Staphylococcus aureus. Three discharges in He, Ar, respectively air were used for water activation. The effect of the treatment time and liquid storage time were both considered. The plasma activated water proved to be efficient for bacterial inhibition, holding its properties for at least 7 days. Hydrogen peroxide was revealed to be the main inhibition agent generated at the plasma liquid-interaction.