Anna A. Brezgunova

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI) and subsequent chronic kidney disease. Nephrotoxicity often develops as a consequence of treatment with commonly prescribed aminoglycoside antibiotics, and remains a significant clinical challenge. One approach to treating AKI and its associated complications is caloric restriction or its pharmacological mimetics. This study aimed to evaluate the effects of caloric restriction mimetic hydroxycitrate (HC) in gentamicin-induced nephrotoxicity, with particular focus on the influence of treatment duration and the underlying molecular mechanisms. In vitro renal tubular epithelial cells models were used to assess HC’s effects on viability, proliferation, and autophagy activation. For in vivo validation, rats with gentamicin-induced AKI received HC treatment via two distinct regimens (3-week and 7-week administration). Experiments on renal tubule cells showed that HC significantly increased cell viability and proliferation and led to the activation of autophagy. In the rat model, only the 7-week administration of HC demonstrated significantly attenuated renal dysfunction in gentamicin-induced AKI. Moreover, it reduced macrophage infiltration, increased renal cell tolerance to apoptosis, activated autophagy, and reduced oxidative stress. Thus, our results indicate that 7-week HC administration could be used as a prophylactic strategy against antibiotic nephrotoxicity, exerting its effects by promoting autophagy, resisting apoptosis, and attenuating oxidative damage.

Objectives: Metabolic substrate deficiency is a key factor in many pathologies, with organ vulnerability depending on specialized metabolic profiles. In this study, we aimed to investigate the impact of deprivation stress on mitochondria and cell functions in different cell types and to assess the potential of fumarate, a tricarboxylic acid (TCA) cycle intermediate, to modulate these stress responses. Methods: We assessed the effects of fumarate on cell proliferation and mitochondrial membrane potential under both normal conditions and serum deprivation in vitro in astrocytes, renal epithelial cells, and hepatic stellate cells. Subsequently, we performed bioinformatic analysis of transcriptomic data for brain, kidney, and liver tissues subjected to ischemia to reveal specific patterns of alterations in energy metabolism. Results: Analysis of mitochondria-associated gene expression revealed striking organ-specific differences in transcriptional responses to ischemia, with a significant decrease in expression of genes related to the TCA cycle and electron transport chain in the kidneys and liver, in contrast to the brain. In an in vitro serum deprivation model, fumarate preserved mitochondrial potential in a cell type-specific manner, with optimal concentrations of 12.5 mM for astrocytes (p < 0.05), and 25 mM for renal (p < 0.01) or hepatic cells (p < 0.01). Under normal conditions, fumarate increased mitochondrial potential in astrocytes (p < 0.0001), with weak or no effect on renal and hepatic cells. Estimation of cell number indicates the effects of fumarate on the proliferation of kidney (p < 0.05) and liver (p < 0.0001) cells in normal conditions and cell death after serum deprivation. Conclusion: Bioinformatic analysis demonstrates that ischemic stress induces fundamentally different transcriptional programs in the brain, kidney, and liver, particularly affecting genes involved in mitochondrial bioenergetics. Complementing these findings, our in vitro data identify fumarate as a metabolically active but organ-dependent candidate for tissue protective strategies in substrate deprivation pathologies, like ischemia.

This study investigated the toxicity of ten polymer materials intended for the development of invasive neural interfaces improving the treatment of neurological diseases. Most of the materials for neural implants can cause traumatization of the surrounding tissue, inflammation, and foreign body reaction. In this study, in vitro and in vivo toxicity assessment was performed for nylon 618 (NY), polycaprolactone (PCL), polyethylene glycol diacrylate (PEGDA), polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polylactide (PLA), thermoplastic polyurethane (TPU), polypropylene (PP), polyethylene terephthalate glycol (PET-G), and polyimide (PI). The biocompatibility of these ten materials was assessed based on cell adhesion, growth and cytotoxicity on neural (PC-12) and fibroblast (NRK-49F) cultures. Furthermore, brain tissue responses to the implanted phantom scaffolds were analyzed in rats. According to these measurements, PI showed the highest compatibility for both cell types. PEGDA exhibited cytotoxic effects, low cell adhesion and the strongest foreign body reaction, including fibrosis and multinucleated cell formation. The other polymers showed lower pathological responses which makes them potentially usable for neural interfacing. We conclude that PEGDA appears to be unsuitable for long-term use due to adverse tissue and cellular reactions, whereas PI, PLA, PDMS and TPU hold promise as materials for safe and effective neural interface applications.

Severe injuries and some pathologies associated with massive bleeding, such as maternal hemorrhage, gastrointestinal and perioperative bleeding, and rupture of an aneurysm, often lead to major blood loss and the development of hemorrhagic shock. A sharp decrease in circulating blood volume triggers a vicious cycle of vasoconstriction and coagulopathy leading to ischemia of all internal organs and, in severe decompensated states, ischemia of the brain and heart. The basis of tissue damage and dysfunction in hemorrhagic shock is an interruption in the supply of oxygen and substrates for energy production to the cells, making the mitochondria a source and target of oxidative stress and proapoptotic signaling. Based on these mechanisms, different strategies are proposed to treat the multiple organ failure that occurs in shock. The main direction of such treatment is to provide the cells with a sufficient amount of substrates that utilize oxidative phosphorylation at different stages and increase the efficiency of energy production by the mitochondria. These strategies include restoring the efficiency of mitochondrial complexes, for example, by restoring the nicotinamide adenine dinucleotide (NAD) pool. Another direction is approaches to minimize oxidative stress as well as apoptosis, which are primarily dependent on the mitochondria. There are also a number of other methods to reduce mitochondrial dysfunction and improve the quality of the mitochondrial population. In this review, we consider such strategies for the treatment of hemorrhagic shock and show the promise of therapeutic approaches aimed at restoring the bioenergetic functions of the cell and protecting mitochondria.

The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of hormone action are poorly characterized. In this study, we investigated the influence of estradiol and progesterone on renal cells during ischemic injury. We performed both in vivo experiments on female and male rats and in vitro experiments on renal tubular cells (RTCs) obtained from the kidneys of intact animals of different sexes. Since mitochondria play an important role in the pathogenesis of AKI, we analyzed the properties of individual mitochondria in renal cells, including the area, roundness, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening time. We found that pre-treatment with progesterone or estradiol attenuated the severity of ischemia/reperfusion (I/R)-induced AKI in female rats, whereas in male rats, these hormones exacerbated renal dysfunction. We demonstrated that the mPTP opening time was higher in RTCs from female rats than that in those from male rats, which may be one of the reasons for the higher tolerance of females to ischemic injury. In RTCs from the kidneys of male rats, progesterone caused mitochondrial fragmentation, which can be associated with reduced cell viability. Thus, therapy with progesterone or estradiol displays quite different effects depending on sex, and could be only effective against ischemic AKI in females.

The development of drugs for the treatment of acute kidney injury (AKI) that could suppress the excessive inflammatory response in damaged kidneys is an important clinical challenge. Recently, synaptamide (N-docosahexaenoylethanolamine) has been shown to exert anti-inflammatory and neurogenic properties. The aim of this study was to investigate the anti-inflammatory effect of synaptamide in ischemic AKI. For this purpose, we analyzed the expression of inflammatory mediators and the infiltration of different leukocyte populations into the kidney after injury, evaluated the expression of the putative synaptamide receptor G-protein-coupled receptor 110 (GPR110), and isolated a population of CD11b/c⁺ cells mainly representing neutrophils and macrophages using cell sorting. We also evaluated the severity of AKI during synaptamide therapy and the serum metabolic profile. We demonstrated that synaptamide reduced the level of pro-inflammatory interleukins and the expression of integrin CD11a in kidney tissue after injury. We found that the administration of synaptamide increased the expression of its receptor GPR110 in both total kidney tissue and renal CD11b/c⁺ cells that was associated with the reduced production of pro-inflammatory interleukins in these cells. Thus, we demonstrated that synaptamide therapy mitigates the inflammatory response in kidney tissue during ischemic AKI, which can be achieved through GPR110 signaling in neutrophils and a reduction in these cells’ pro-inflammatory interleukin production.