title: Development of progressive albuminuria in male Munich Wistar Frömter rats is androgen dependent.
abstract: Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (-55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (-71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham (P < 0.0008, respectively) and expression decreased significantly in MWF OxTF (P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Laura
authors.initials: L
authors.lastname: Herlan
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Unland
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Langer
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Leonard
authors.initials: L
authors.lastname: Schulte
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schütten
authors.affiliation: Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, Madrid, Spain; and.
authors.forename: Concha F
authors.initials: CF
authors.lastname: García-Prieto
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Kossmehl
authors.affiliation: Instituto Pluridisciplinar, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Fernández-Alfonso
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany; Reinhold.kreutz@charite.de.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000419:Albuminuria / Q000139:chemically induced*; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D008297:Male; D009919:Orchiectomy / Q000009:adverse effects*; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D018709:Statistics, Nonparametric; D013481:Superoxides / Q000378:metabolism; D013739:Testosterone / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood
chemical_list: D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D013481:Superoxides; D013739:Testosterone; D005485:Flutamide
keywords: albuminuria; androgens; genetics; kidney; testosterone