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This document discusses the importance of oxygen for cells and tissues and how they sense a lack of oxygen, known as hypoxia, in order to adapt to this life-threatening condition. The discovery of the hormone erythropoietin and the transcription factor hypoxia-inducible factor (HIF) has shed light on how cells sense oxygen availability through enzymes called HIF hydroxylases. These findings were awarded the Nobel Prize in 2019. Small molecule inhibitors of HIF hydroxylases have been developed for clinical use in anemias caused by erythropoietin deficiency. This special issue of Pflugers Archive explores other potential applications of HIF hydroxylase inhibitors and their effects on cellular functions beyond erythropoietin production. These include effects on metabolism, glycolysis, immune response, steroidogenesis, intercellular communication, and the role of reactive oxygen species in oxygen sensing. [Extracted from the article]

Renal erythropoietin (Epo)-producing (REP) cells represent a rare and incompletely understood cell type. REP cells are fibroblast-like cells located in close proximity to blood vessels and tubules of the corticomedullary border region. Epo mRNA in REP cells is produced in a pronounced "on–off" mode, showing transient transcriptional bursts upon exposure to hypoxia. In contrast to "ordinary" fibroblasts, REP cells do not proliferate ex vivo, cease to produce Epo, and lose their identity following immortalization and prolonged in vitro culture, consistent with the loss of Epo production following REP cell proliferation during tissue remodelling in chronic kidney disease. Because Epo protein is usually not detectable in kidney tissue, and Epo mRNA is only transiently induced under hypoxic conditions, transgenic mouse models have been developed to permanently label REP cell precursors, active Epo producers, and inactive descendants. Future single-cell analyses of the renal stromal compartment will identify novel characteristic markers of tagged REP cells, which will provide novel insights into the regulation of Epo expression in this unique cell type. [ABSTRACT FROM AUTHOR]

Imenez Silva and Mohebbi summarize recent concepts how the kidney contributes to acid-base homeostasis and how acidosis may impact on kidney disease progression. Arguably, the kidneys are central organs for controlling and regulating the homeostasis of electrolytes, metabolites, and processes critical for normal function of most organs. Kidney disease affects worldwide 10-12% of the population and its prevalence is expected to rather increase with the aging of populations and the rise of conditions such as diabetes and hypertension that can cause or accelerate kidney disease [[4]]. [Extracted from the article]

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance. [ABSTRACT FROM AUTHOR]

The recent bestowal of the Nobel Prize 2019 in Physiology or Medicine to Gregg L. Semenza, Sir Peter J. Ratcliffe, and William G. Kaelin Jr. celebrates a series of remarkable discoveries that span from the physiological research question on how oxygen deficiency (hypoxia) induces the red blood cell forming hormone erythropoietin (Epo) to the first clinical application of a novel family of Epo-inducing drugs to treat patients suffering from renal anemia. This review looks back at the most important findings made by the three Nobel laureates, highlights current research trends, and sheds an eye on future perspectives of hypoxia research, including emerging and potential clinical applications. [ABSTRACT FROM AUTHOR]

Later, renal peritubular fibroblasts were identified as production sites for EPO and EPO gene transcription was recognized as the essential control process for EPO production. Completely unclear and speculative at that time was the functional link between hypoxia and the activation of EPO gene transcription. First, a new heterodimeric transcription factor that appeared during hypoxia and bound to the EPO gene enhancer was discovered and characterized. [Extracted from the article]

Highlights from the article: It is well established that the number of renin-secreting cells can increase by hyperplasia and also by reversible metaplastic transformation of "silent" renin-producing cells into active renin producers and vice versa [[4]]. They also found that deletion of Gs protein in renin cells did not destroy the cells but instead caused a phenotype switch to a renin-negative and fibroblast-like cell.