Hypoxia-inducible factor-2 stabilization is not sufficient to induce erythropoietin production in deeper medullary fibroblasts.

Under hypoxaemic conditions, cortical fibroblasts primarily produce erythropoietin (EPO). However, we have previously shown that most interstitial fibroblasts positive for platelet-derived growth factor receptor β (PDGFR-β) in all kidney zones are also able to produce EPO. Therefore, we wondered if either the physiological stimuli might not be sufficient to stabilize the hypoxia-inducible factor (HIF)-2 in medullary fibroblasts or if different expression patterns or functions of the HIF-regulating prolyl-4-hydroxylases (PHD) 2 and 3 might explain the restrictive EPO cell recruitment.

Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.

Chronic kidney disease (CKD) is a global health epidemic that greatly increases mortality due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiac injury in CKD. High serum levels of fibroblast growth factor (FGF) 23 in patients with CKD may contribute mechanistically to the pathogenesis of LVH by activating FGF receptor (FGFR) 4 signaling in cardiac myocytes.

Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and -independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study.

Study Design: Prospective observational study.

Localization and characterization of proenkephalin-A as a potential biomarker for kidney disease in murine and human kidneys.

Introduction: Exact measurement of renal function is essential for the treatment of patients. Elevated serum-creatinine levels, while established, are influenced by other parameters and show a significant time-lag. This drives the search for novel biomarkers of renal function and injury.

The fate of erythropoietin-producing cells: another piece of the puzzle.

In this issue, Kaneko et al. reported the generation of a mouse line that allows for the labeling of cells under control of the erythropoietin (Epo) gene promotor. The authors show that Epo-producing cells become proliferating, profibrotic cells after kidney injury and lose their ability to produce Epo.

Flexible and multifaceted: the plasticity of renin-expressing cells.

The protease renin, the key enzyme of the renin-angiotensin-aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located in the walls of the afferent arterioles at their entrance into the glomeruli. When the body's demand for renin rises, the renin production capacity of the kidneys commonly increases by induction of renin expression in vascular smooth muscle cells and in extraglomerular mesangial cells. These cells undergo a reversible metaplastic cellular transformation in order to produce renin.

Intact prostaglandin signaling through EP2 and EP4 receptors in stromal progenitor cells is required for normal development of the renal cortex in mice.

Cyclooxygenase (Cox) inhibitors are known to have severe side effects during renal development. These consist of reduced renal function, underdeveloped subcapsular glomeruli, interstitial fibrosis, and thinner cortical tissue. Global genetic deletion of Cox-2 mimics the phenotype observed after application of Cox inhibitors.

Prolyl-4-hydroxylases 2 and 3 control erythropoietin production in renin-expressing cells of mouse kidneys.

Activation of the hypoxia-signalling pathway induced by deletion of the ubiquitin-ligase von Hippel-Lindau protein causes an endocrine shift of renin-producing cells to erythropoietin (EPO)-expressing cells. However, the underlying mechanisms have not yet been investigated. Since oxygen-regulated stability of hypoxia-inducible transcription factors relevant for EPO expression is dependent on the activity of prolyl-4-hydroxylases (PHD) 2 and 3, this study aimed to determine the relevance of different PHD isoforms for the EPO expression in renin-producing cells in vivo.

Endothelin receptors in renal interstitial cells do not contribute to the development of fibrosis during experimental kidney disease.

Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis.

Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice.

Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor β1 (TGFβ1) is considered a central trigger for kidney fibrosis.

Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo.

Genetic induction of hypoxia signaling by deletion of the von Hippel-Lindau (Vhl) protein in mesenchymal PDGFR-β cells leads to abundant HIF-2 dependent erythropoietin (EPO) expression in the cortex and outer medulla of the kidney. This rather unique feature of kidney PDGFR-β cells promote questions about their special characteristics and general functional response to hypoxia. To address these issues, we characterized kidney PDGFR-β EPO expressing cells based on additional cell markers and their gene expression profile in response to hypoxia signaling induced by targeted deletion of Vhl or exposure to low oxygen and carbon monoxide respectively, and after unilateral ureteral obstruction.