title: Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria.
abstract: Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Riera
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and.
authors.forename: Lidia
authors.initials: L
authors.lastname: Anguiano
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and.
authors.forename: Sergi
authors.initials: S
authors.lastname: Clotet
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and.
authors.forename: Heleia
authors.initials: H
authors.lastname: Roca-Ho
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Rebull
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Pascual
authors.affiliation: Department of Nephrology, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; and Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Madrid, Spain msoler@parcdesalutmar.cat.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Soler
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004872:Ergocalciferols / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D016688:Mice, Inbred NOD; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D011507:Proteinuria / Q000517:prevention & control; D011897:Random Allocation; D012083:Renin / Q000378:metabolism
chemical_list: D004872:Ergocalciferols; C084656:paricalcitol; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: angiotensin-converting enzyme 2; animal model; diabetic nephropathy; renin-angiotensin system