ABSTRACT
Renal erythropoietin-producing cells (REPCs) remain in the kidneys of patients with chronic kidney disease, but these cells do not produce sufficient erythropoietin in response to hypoxic stimuli. Treatment with HIF stabilizers rescues erythropoietin production in these cells, but the mechanisms underlying the decreased response of REPCs in fibrotic kidneys to anemic stimulation remain elusive. Here, we show that fibroblast-like FOXD1+ progenitor-derived kidney pericytes, which are characterized by the expression of α1 type I collagen and PDGFRß, produce erythropoietin through HIF2α regulation but that production is repressed when these cells differentiate into myofibroblasts. DNA methyltransferases and erythropoietin hypermethylation are upregulated in myofibroblasts. Exposure of myofibroblasts to nanomolar concentrations of the demethylating agent 5-azacytidine increased basal expression and hypoxic induction of erythropoietin. Mechanistically, the profibrotic factor TGF-ß1 induced hypermethylation and repression of erythropoietin in pericytes; these effects were prevented by 5-azacytidine treatment. These findings shed light on the molecular mechanisms underlying erythropoietin repression in kidney myofibroblasts and demonstrate that clinically relevant, nontoxic doses of 5-azacytidine can restore erythropoietin production and ameliorate anemia in the setting of kidney fibrosis in mice.
Subject(s)
Azacitidine/pharmacology , DNA Modification Methylases/antagonists & inhibitors , Erythropoietin/biosynthesis , Myofibroblasts/metabolism , Pericytes/metabolism , Renal Insufficiency, Chronic/drug therapy , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Collagen Type I/biosynthesis , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , Erythropoietin/genetics , Fibrosis , Mice , Mice, Transgenic , Myofibroblasts/pathology , Pericytes/pathology , Receptor, Platelet-Derived Growth Factor beta/genetics , Receptor, Platelet-Derived Growth Factor beta/metabolism , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathologyABSTRACT
Pericytes are the major source of scar-producing myofibroblasts following kidney injury; however, the mechanisms of this transition are unclear. To clarify this, we examined Collagen 1 (α1)-green fluorescent protein (GFP) reporter mice (pericytes and myofibroblasts express GFP) following ureteral obstruction or ischemia-reperfusion injury and focused on the role of platelet-derived growth factor (PDGF)-receptor (PDGFR) signaling in these two different injury models. Pericyte proliferation was noted after injury with reactivation of α-smooth muscle actin expression, a marker of the myofibroblast phenotype. PDGF expression increased in injured tubules, endothelium, and macrophages after injury, whereas PDGFR subunits α and ß were expressed exclusively in interstitial GFP-labeled pericytes and myofibroblasts. When PDGFRα or PDGFRß activation was inhibited by receptor-specific antibody following injury, proliferation and differentiation of pericytes decreased. The antibodies also blunted the injury-induced transcription of PDGF, transforming growth factor ß1, and chemokine CCL2. They also reduced macrophage infiltration and fibrosis. Imatinib, a PDGFR tyrosine kinase inhibitor, attenuated pericyte proliferation and kidney fibrosis in both fibrogenic models. Thus, PDGFR signaling is involved in pericyte activation, proliferation, and differentiation into myofibroblasts during progressive kidney injury. Hence, pericytes may be a novel target to prevent kidney fibrosis by means of PDGFR signaling blockade.
Subject(s)
Fibrosis/etiology , Kidney Diseases/pathology , Myofibroblasts/pathology , Pericytes/pathology , Receptors, Platelet-Derived Growth Factor/metabolism , Reperfusion Injury/pathology , Ureteral Obstruction/pathology , Animals , Cell Differentiation , Cell Proliferation , Kidney Diseases/etiology , Mice , Signal Transduction/physiologySubject(s)
Colonic Pseudo-Obstruction/diagnostic imaging , Aged , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic/adverse effects , Colonic Pseudo-Obstruction/etiology , Humans , Liver Neoplasms/complications , Liver Neoplasms/therapy , Male , Tomography, X-Ray ComputedSubject(s)
Acute Kidney Injury/diagnosis , Hypercalcemia/diagnosis , Neoplasms, Multiple Primary/diagnosis , Sarcoidosis/diagnosis , Splenic Diseases/diagnosis , Splenic Neoplasms/diagnosis , Abdomen/diagnostic imaging , Acute Kidney Injury/pathology , Aged , Calcitriol/blood , Creatinine/blood , Female , Granuloma/diagnosis , Granuloma/pathology , Granuloma/surgery , Humans , Hypercalcemia/pathology , Magnetic Resonance Imaging , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/surgery , Parathyroid Glands/diagnostic imaging , Parathyroid Hormone/blood , Sarcoidosis/pathology , Sarcoidosis/surgery , Splenectomy , Splenic Diseases/pathology , Splenic Diseases/surgery , Splenic Neoplasms/pathology , Splenic Neoplasms/surgery , Treatment Outcome , UltrasonographyABSTRACT
The ratio of aldosterone-to-renin activity is currently recommended as a screening test for primary aldosteronism (PA). There are many factors interfering the interpretation of aldosterone-renin ratio (ARR) and could hamper in-time diagnosis of PA. Here, we first report a patient with underlying Page phenomenon and an accidentally disclosed adrenal incidentaloma. High renin secretion from Page phenomenon had masked higher ARR into normal ARR obscuring the diagnosis of PA. However, adrenal venous sampling (AVS) confirmed the autonomous aldosterone secretion with left adrenal vein plasma aldosterone concentration (PAC) 124.1 ng/dl and a lateralization ratio 3.3. AVS may discriminate masked PA due to high renin secretion from Page kidney. It is suggested that clinicians should cautiously interpret aldosterone-renin ratio and consider diagnostic AVS if hyperaldosteronism is highly suspected especially in the background of other secondary hypertension.
Subject(s)
Adrenal Gland Neoplasms/complications , Hematoma/complications , Hyperaldosteronism/complications , Hypertension, Renal/etiology , Adrenal Gland Neoplasms/blood , Adrenal Gland Neoplasms/diagnostic imaging , Adrenal Glands/blood supply , Adrenal Glands/metabolism , Adult , Aldosterone/blood , Aldosterone/metabolism , Hematoma/diagnostic imaging , Humans , Hyperaldosteronism/blood , Hypertension, Renal/blood , Hypertension, Renal/diagnostic imaging , Incidental Findings , Kidney/diagnostic imaging , Male , Renin/blood , Renin/metabolism , Tomography, X-Ray Computed , VeinsSubject(s)
Colitis/etiology , Colonic Neoplasms/complications , Emphysema/etiology , Lymphoma, Large B-Cell, Diffuse/complications , Air , Colectomy/methods , Colitis/diagnostic imaging , Colitis/pathology , Colitis/surgery , Colonic Neoplasms/diagnostic imaging , Colonic Neoplasms/pathology , Colonic Neoplasms/surgery , Emergencies , Emphysema/diagnostic imaging , Emphysema/pathology , Emphysema/surgery , Fatal Outcome , Humans , Lymphatic Metastasis , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/surgery , Male , Middle Aged , Portal Vein/pathology , Tomography, X-Ray ComputedSubject(s)
IgA Vasculitis/diagnosis , IgA Vasculitis/pathology , Endoscopy, Gastrointestinal , Histocytochemistry , Humans , Intestinal Mucosa/pathology , Intestine, Small/pathology , Leg/pathology , Male , Middle Aged , Radiography, Abdominal , Skin/pathology , Tomography, X-Ray Computed , Vasculitis/pathologyABSTRACT
A 69-year-old woman with history of operation for stress urinary incontinence presented with left flank soreness. Physical examination revealed knocking tenderness at left costal-vertebral angle. Her serum creatinine level was 1.2 mg/dL and urine analysis was negative. Ultrasonography showed left hydronephrosis, and computed tomography scan revealed ureterosciatic herniation. An antegrade placement of the indwelling ureteral stent was performed. After 3 months, the double J catheter was removed and the patient recovered without recurrent symptoms.