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Background and Objective: Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is an important mechanism of diabetic kidney disease (DKD). Single-nucleus RNA sequencing (snRNA-seq) technology is a high-throughput sequencing analysis technique for RNA at the level of a single cell nucleus. Here, our DKD mouse kidney single-cell RNA sequencing conveys a more comprehensive mitochondrial profile, which helps us further understand the therapeutic response of this unique organelle family to drugs. Methods: After high fat diet (HFD), mice were intraperitoneally injected with streptozotocin (STZ) to induce DKD, and then divided into three subsets: CON (healthy) subset, DKD (vehicle) subset, and LST (losartan; 25 mg/kg/day) subset. Divide HK-2 cell into LG (low glucose; 5 mM) and HG (high glucose; 30 mM) and HG + LST (losartan; 1 µ M) subsets. snRNA-seq was performed on the renal tissues of LST and DKD subset mice. To reveal the effects of losartan on gene function and pathway changes in renal tubular mitochondria, Gene Ontology (GO) enrichment analysis and GSEA/GSVA scoring were performed to analyze the specific response of proximal tubular (PT) cell mitochondria to losartan treatment, including key events in mitochondrial homeostasis such as mitochondrial morphology, dynamics, mitophagy, autophagic flux, mitochondrial respiratory chain, apoptosis, and ROS generation. Preliminary validation through in vitro and in vivo experiments, including observation of changes in mitochondrial morphology and dynamics using probes such as Mitotracker Red, and evaluation of the effect of losartan on key events of mitochondrial homeostasis perturbation using electron microscopy, laser confocal microscopy, immunofluorescence, and Western blotting. Detection of autophagic flux in cells by transfecting Ad-mCherry-GFP-LC3B dual fluorescence labeled adenovirus. Various fluorescent probes and energy detector are used to detect mitochondrial apoptosis, ROS, and respiration of mitochondrion. Results: Through the single-cell atlas of DKD mouse kidneys, it was found that losartan treatment significantly increased the percentage of PT cells. Gene Ontology (GO) enrichment analysis of differentially expressed genes showed enrichment of autophagy of mitochondrion pathway. Further GSEA analysis and GSVA scoring revealed that mitophagy and other key mitochondrial perturbation events, such as ROS production, apoptosis, membrane potential, adenosine triphosphate (ATP) synthesis, and mitochondrial dynamics, were involved in the protective mechanism of losartan on PT cells, thereby improving mitochondrial homeostasis. Consistent results were also obtained in mice and cellular experiments. In addition, we highlighted a specific renal tubular subpopulation with mitophagy phenotype found in single-cell data, and preliminarily validated it with co-localization and increased expression of Pink1 and Gclc in kidney specimens of DKD patients treated with losartan. Conclusions: Our research suggests that scRNA-seq can reflect the multifaceted mitochondrial landscape of DKD renal tubular cells after drug treatment, and these findings may provide new targets for DKD therapy at the organelle level. [ABSTRACT FROM AUTHOR]

Hypertension is a global health concern not only correlated with cardiovascular complications, but also with impaired bone metabolism, potentially affecting healing at the bone–implant interface. Losartan, an angiotensin II receptor blocker (ARB) commonly prescribed for hypertension, has shown beneficial effects on bone healing in spontaneously hypertensive rats (SHRs). However, the influence of hypertension and ARBs like losartan on the bone cellular response at the bone–implant interface remains underexplored. Methods: A total of 32 rats were included in this study: 16 SHRs, with 8 receiving losartan (30 mg/kg daily) and 8 receiving no treatment, and 16 normotensive Wistar rats, with 8 receiving losartan and 8 receiving no treatment. After one week of treatment, titanium implants were placed into the tibia of all the animals. The bone–implant interface was assessed 60 days post-implantation using micro-computed tomography (µCT) and an immunohistochemical analysis. Results: (i) The ARB treatment significantly increased the bone volume and bone–implant contact in the SHRs receiving losartan compared to the untreated SHRs. (ii) Consistent with the µCT findings, the immunohistochemistry further confirmed regular bone turnover and increased osteocalcin (OC) mineralization in the treated SHRs. In contrast, no alterations in the bone microarchitecture were noted in the Wistar rats treated with losartan. Conclusions: The results suggest that losartan, an ARB drug, improves bone volume and bone turnover at the bone–implant interface in SHRs. [ABSTRACT FROM AUTHOR]

The synthesis of 4-(1H-tetrazol-5-yl)-2-(p-tolyl)quinoline 4 as a possible modification of the biphenyltetrazole substructure of losartan 1 is described. The transformation of 2-(p-tolyl)quinoline-4-carbonitrile 3 to the corresponding tetrazole 4 was carried out by the reaction of trimethysilyl azide and dibutyltin oxide as a catalyst in refluxing toluene. The title compound (4) was characterized by IR, 1H NMR, 13C NMR, and HRMS. [ABSTRACT FROM AUTHOR]

Angiotensin II receptor antagonists are tetrazole derivatives used in the treatment of high blood pressure, and are also indicated for the treatment of heart failure (NYHA class II-IV). They are used alone or in combination with other classes of antihypertensives or diuretics for the effective management of high blood pressure. In this study, we aim to evaluate the thermal stability and degradation kinetics for the principal compounds used in therapy from this class, namely telmisartan, valsartan, olmesartan medoxomil, and losartan potassium. To obtain the thermoanalytical data for the kinetic investigations, the TG and DTG curves were registered at five different heating rates (β = 2, 4, 6, 8, and 10 °C min−1). The kinetic methods used were a preliminary ASTM E698 method and two isoconversional methods: Flynn–Wall–Ozawa and Friedman. For each molecule, the results showed complex decomposition processes consisting of complex reaction sequences. [ABSTRACT FROM AUTHOR]