The review describes functional and structural features of different isoforms of prolactin receptor, mechanisms of signaling pathway activation, and molecular messengers involved in the transmission...

Cholestasis of pregnancy is a pathology associated with disruptions in the bile flow and dysregulation of salt and water homeostasis. Prolactin is one of the most important regulators of salt and...

Fibrosis is a severe complication of many acute and chronic kidney pathologies. According to current concepts, an imbalance in the synthesis and degradation of the extracellular matrix by fibroblasts is considered the key cause of the induction and progression of fibrosis. Nevertheless, inflammation associated with the damage of tissue cells is among the factors promoting this pathological process. Most of the mechanisms accompanying fibrosis development are controlled by various hormones, which makes humoral regulation an attractive target for therapeutic intervention. In this vein, it is particularly interesting that the kidney is the source of many hormones, while other hormones regulate renal functions. The normal kidney physiology and pathogenesis of many kidney diseases are sex-dependent and thus modulated by sex hormones. Therefore, when choosing therapy, it is necessary to focus on the sex-associated characteristics of kidney functioning. In this review, we considered renal fibrosis from the point of view of vasoactive and reproductive hormone imbalance. The hormonal therapy possibilities for the treatment or prevention of kidney fibrosis are also discussed.

The development of liver fibrosis is one of the most severe and life-threatening outcomes of chronic liver disease (CLD). For targeted therapy of CLD, it is highly needed to reveal molecular targets for normalizing metabolic processes impaired in damaged liver and associated with fibrosis. In this study, we investigated the morphological and biochemical changes in rat liver models of fibrosis induced by chronic administration of thioacetamide, carbon tetrachloride, bile duct ligation (BDL), and ischemia/reperfusion (I/R), with a specific focus on carbohydrate and energy metabolism. Changes in the levels of substrates and products, as well as enzyme activities of the major glucose metabolic pathways (glycolysis, glucuronidation, and pentose phosphate pathway) were examined in rat liver tissue after injury. We examined key markers of oxidative energy metabolism, such as the activity of the Krebs cycle enzymes, and assessed mitochondrial respiratory activity. In addition, pro- and anti-oxidative status was assessed in fibrotic liver tissue. We found that 6 weeks of exposure to thioacetamide, carbon tetrachloride, BDL or I/R resulted in a decrease in the activity of glycolytic enzymes, retardation of mitochondrial respiration, elevation of glucuronidation, and activation of pentose phosphate pathways, accompanied by a decrease in antioxidant activity and the onset of oxidative stress in rat liver. Resemblance and differences in the changes in the fibrosis models used are described, including energy metabolism alterations and antioxidant status in the used fibrosis models. The least pronounced changes in glucose metabolism and mitochondrial functions in the I/R and thioacetamide models were associated with the least advanced fibrosis. Ultimately, liver fibrosis significantly altered the metabolic profile in liver tissue and the flux of glucose metabolic pathways, which could be the basis for targeted therapy of liver fibrosis in CLD caused by toxic, cholestatic, or I/R liver injury.

Stimulus-dependent elevation of intracellular Ca²⁺ affects gene expression via well-documented calmodulin-mediated signaling pathways. Recently, we found that the addition of extra- and intracellular Ca²⁺ chelators increased, rather than decreased, the number of genes expressed, and that this is affected by the elevation of [Na⁺]_i/[K⁺]_i-ratio. This assumes the existence of a novel Na⁺_i/K⁺_i-mediated Ca²⁺_i-independent mechanism of excitation-transcription coupling. To identify upstream Na⁺_i/K⁺_i-sensitive genes, we examined the kinetics of transcriptomic changes in human umbilical vein endothelial cells (HUVEC) subjected to Na,K-ATPase inhibition by ouabain or K⁺-free medium. According to our data, microRNAs, transcription factors, and proteins involved in immune response and inflammation might be considered as key components of Na⁺_i/K⁺_i-mediated excitation-transcription coupling. Special attention was focused on the FOS gene and the possible mechanism of transcription regulation via G-quadruplexes, non-canonical secondary structures of nucleic acids, whose stability depends on [Na⁺]_i/[K⁺]_i-ratio. Verification of the [Na⁺]_i/[K⁺]_i-sensitive transcription regulation mechanism should be continued in forthcoming studies.

Participation of Na⁺/K⁺-ATPase in the natriuretic effect of prolactin in a cholestasis of pregnancy model was investigated. The Na⁺/K⁺-ATPase activity in rat kidney medulla, where active sodium reabsorption occurs, decreased in the model of cholestasis of pregnancy and other hyperprolactinemia types compared with intact animals. This effect was not connected with the protein level of α1- and β-subunits of Na⁺/K⁺-ATPase measured by Western blotting in the kidney medulla. Decrease in Na⁺/K⁺-ATPase activity in the kidney cortex was not significant, as well as decrease in the quantity of mRNA and proteins of the α1- and β-subunits of Na⁺/K⁺-ATPase. There were no correlations between the Na⁺/K⁺-ATPase activity and sodium clearance, although sodium clearance increased significantly in the model of cholestasis of pregnancy and other hyperprolactinemia groups under conditions of stable glomerular filtration rate measured by creatinine clearance. We conclude that the Na⁺/K⁺-ATPase is not the only mediator of the natriuretic effect of prolactin in the model of cholesta- sis of pregnancy.