title: Plasma heme-induced renal toxicity is related to a capillary rarefaction.
abstract: Severe hypertension can lead to malignant hypertension (MH) with renal thrombotic microangiopathy and hemolysis. The role of plasma heme release in this setting is unknown. We aimed at evaluating the effect of a mild plasma heme increase by hemin administration in angiotensin II (AngII)-mediated hypertensive rats. Prevalence of MH and blood pressure values were similar in AngII and AngII + hemin groups. MH rats displayed a decreased renal blood flow (RBF), increased renal vascular resistances (RVR), and increased aorta and interlobar arteries remodeling with a severe renal microcirculation assessed by peritubular capillaries (PTC) rarefaction. Hemin-treated rats with or without AngII displayed also a decreased RBF and increased RVR explained only by PCT rarefaction. In AngII rats, RBF was similar to controls (with increased RVR). PTC density appeared strongly correlated to tubular damage score (rho = -0.65, p < 0.0001) and also renal Heme Oygenase-1 (HO-1) mRNA (rho = -0.67, p < 0.0001). HO-1 was expressed in PTC and renal tubules in MH rats, but only in PTC in other groups. In conclusion, though increased plasma heme does not play a role in triggering or aggravating MH, heme release appears as a relevant toxic mediator leading to renal impairment, primarily through PTC endothelial dysfunction rather than direct tubular toxicity.
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Service d'Explorations Fonctionnelles Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.|Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Nahid
authors.initials: N
authors.lastname: Tabibzadeh
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Service d'Explorations Fonctionnelles Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.|Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Estournet
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.|Ecole Vétérinaire de Maisons Alfort, France.
authors.forename: Héloïse
authors.initials: H
authors.lastname: Bilbault
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Girshovich
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Service d'Explorations Fonctionnelles Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.|Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Institut de Cardiologie, Pitié-Salpêtrière Hospital (AP-HP), Institute of Cardiometabolism and Nutrition (ICAN), ACTION Study Group, INSERM UMRS 1166, Paris, France.
authors.forename: Nadjib
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Centre de la drépanocytose, service de médecine interne, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Lionnet
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Paris, France.|Service d'Explorations Fonctionnelles Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.|Institut National de la Sante et de la Recherche Médicale, UMR-S 1155, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
mesh_terms: D000818:Animals; D006418:Heme / Q000633:toxicity*; D006427:Hemin / Q000008:administration & dosage; D006973:Hypertension / Q000150:complications*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D000073436:Microvascular Rarefaction / Q000473:pathology*; D010949:Plasma / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation
chemical_list: D006418:Heme; D006427:Hemin