title: Evidence for pericyte origin of TSC-associated renal angiomyolipomas and implications for angiotensin receptor inhibition therapy.
abstract: Nearly all patients with tuberous sclerosis complex (TSC) develop renal angiomyolipomas, although the tumor cell of origin is unknown. We observed decreased renal angiomyolipoma development in patients with TSC2- polycystic kidney disease 1 deletion syndrome and hypertension that were treated from an early age with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers compared with patients who did not receive this therapy. TSC-associated renal angiomyolipomas expressed ANG II type 1 receptors, platelet-derived growth factor receptor-β, desmin, α-smooth muscle actin, and VEGF receptor 2 but did not express the adipocyte marker S100 or the endothelial marker CD31. Sera of TSC patients exhibited increased vascular mural cell-secreted peptides, such as VEGF-A, VEGF-D, soluble VEGF receptor 2, and collagen type IV. These findings suggest that angiomyolipomas may arise from renal pericytes. ANG II treatment of angiomyolipoma cells in vitro resulted in an exaggerated intracellular Ca(2+) response and increased proliferation, which were blocked by the ANG II type 2 receptor antagonist valsartan. Blockade of ANG II signaling may have preventative therapeutic potential for angiomyolipomas.
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Siroky
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Dixon
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Reichert
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom;
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hellmann
authors.affiliation: Novartis Institute of Biomedical Research, Cambridge, Massachusetts;
authors.forename: Thiruvamoor
authors.initials: T
authors.lastname: Ramkumar
authors.affiliation: Daiichi Sankyo, Parsippany, New Jersey;
authors.forename: Zenta
authors.initials: Z
authors.lastname: Tsuchihashi
authors.affiliation: Department of Medicine, Division of Nephrology, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina;
authors.forename: Marlene
authors.initials: M
authors.lastname: Bunni
authors.affiliation: Department of Medicine, Division of Nephrology, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina;
authors.forename: Joshua
authors.initials: J
authors.lastname: Dillon
authors.affiliation: Department of Medicine, Division of Nephrology, Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina;
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
authors.affiliation: Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom;
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.affiliation: Tuberous Sclerosis Complex Center of Excellence, Le Bonheur Children's Hospital, University of Tennessee College of Medicine, Memphis, Tennessee jbissler@uthsc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
mesh_terms: D018207:Angiomyolipoma / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D020286:Pericytes / Q000473:pathology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014402:Tuberous Sclerosis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D014633:Valine; D002118:Calcium
keywords: angiomyolipoma; angiotensin II type 1 receptor; mammalian target of rapamycin; pericyte; perivascular epithelioid cell tumor; tuberous sclerosis complex