title: Knockdown of parathyroid hormone related protein in smooth muscle cells alters renal hemodynamics but not blood pressure.
abstract: Parathyroid hormone-related protein (PTHrP) belongs to vasoactive factors that regulate blood pressure and renal hemodynamics both by reducing vascular tone and raising renin release. PTHrP is expressed in systemic and renal vasculature. Here, we wanted to assess the contribution of vascular smooth muscle cell endogenous PTHrP to the regulation of cardiovascular and renal functions. We generated a mouse strain (SMA-CreERT2/PTHrPL2/L2 or premutant PTHrPSM-/-), which allows temporally controlled, smooth muscle-targeted PTHrP knockdown in adult mice. Tamoxifen treatment induced efficient recombination of PTHrP-floxed alleles and decreased PTHrP expression in vascular and visceral smooth muscle cells of PTHrPSM-/- mice. Blood pressure remained unchanged in PTHrPSM-/- mice, but plasma renin concentration and creatinine clearance were reduced. Renal hemodynamics were further analyzed during clearance measurements in anesthetized mice. Conditional knockdown of PTHrP decreased renal plasma flow and glomerular filtration rate with concomitant reduction in filtration fraction. Similar measurements were repeated during acute saline volume expansion. Saline volume expansion induced a rise in renal plasma flow and reduced filtration fraction; both were blunted in PTHrPSM-/- mice leading to impaired diuresis. These findings show that endogenous vascular smooth muscle PTHrP controls renal hemodynamics under basal conditions, and it is an essential factor in renal vasodilation elicited by saline volume expansion.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U682, Equipe Cancer du rein et Physiopathologie rénale, Faculté de Médecine, Strasbourg, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Raison
authors.forename: Catherine
authors.initials: C
authors.lastname: Coquard
authors.forename: Mazène
authors.initials: M
authors.lastname: Hochane
authors.forename: Jacques
authors.initials: J
authors.lastname: Steger
authors.forename: Thierry
authors.initials: T
authors.lastname: Massfelder
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulin
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Karaplis
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Helwig
authors.forename: Mariette
authors.initials: M
authors.lastname: Barthelmebs
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology*; D001810:Blood Volume / Q000502:physiology; D017931:DNA Primers; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012079:Renal Circulation / Q000235:genetics* / Q000502:physiology*; D012083:Renin / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D044162:Parathyroid Hormone-Related Protein; D013629:Tamoxifen; D012083:Renin
keywords: blood pressure; parathyroid hormone-related protein; renal hemodynamics; saline volume expansion