Herlan Laura, Unland Johannes, Langer Sebastian, Schulte Leonard, Schütten Sabrina, García-Prieto Concha F, Kossmehl Peter, Fernández-Alfonso Maria S, Schulz Angela, Kreutz Reinhold
Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité - Universitätsmedizin Berlin, Berlin, Germany;
Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, Madrid, Spain; and.
Physiol Genomics. 2015 Jul;47(7):281-9. doi: 10.1152/physiolgenomics.00008.2015. Epub 2015 May 12.
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.
慕尼黑维斯特大鼠（MWF）会出现自发性蛋白尿，这与常染色体遗传位点相关，并且在雌性和雄性动物中分别继承了肾单位缺陷。然而，蛋白尿和肾脏损伤在雄性中明显更为显著。在此，我们测试了雄激素和雄激素受体是否会影响雄性MWF大鼠的蛋白尿。我们首先在一项初步研究中表明，雄性MWF大鼠的睾丸切除术（Ox）导致尿白蛋白排泄（UAE）显著降低，而在MWF Ox大鼠中持续补充睾酮会使UAE水平与假手术（Sham）的MWF大鼠相似。随后，我们在雄性MWF大鼠和正常Wistar大鼠之间进行了一项比较性主要研究，以评估雄激素受体对成年动物（直至18周龄）UAE发展的影响。与Wistar Sham相比，MWF Sham的UAE显著增加（48.30±6.16 vs. 0.42±0.08 mg/24 h，P<0.0001）。与MWF Sham相比，MWF Ox的UAE显著降低（-55%，P<0.0001）。在补充睾酮并接受雄激素受体拮抗剂氟他胺治疗的MWF Ox动物（OxTF）中，18周时的UAE甚至比MWF Ox更低（-71%，P<0.01），且与年龄匹配的雌性MWF相似。与Wistar Sham相比，MWF Sham中肾小管损伤标志物Kim1和NGAL的mRNA表达增加（分别为P<0.0008），而在MWF OxTF中表达显著降低（分别为P<0.0004）。因此，MWF大鼠蛋白尿发展中的性别差异可归因于雄性大鼠体内的睾酮和雄激素受体。
