Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Hokkaido 060-0818, Japan.
Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan.
Exp Biol Med (Maywood). 2021 Jun;246(11):1318-1329. doi: 10.1177/1535370221996010. Epub 2021 Feb 27.
Sex hormones help in maintaining proper immunity as well as renal homeostasis in mammals, and these multi-functional properties characterize the onset of sex-dependent diseases. To clarify the contribution of sex hormones to autoimmune disease-related renal pathogenesis, BXSB/MpJ- was investigated as a murine autoimmune glomerulonephritis model. BXSB/MpJ- and its wild-type, BXSB/MpJ- were castrated or sham-operated at three weeks and examined until six months of age. Both castrated strains showed significantly lower serum testosterone levels and body weights than sham-operated mice. Castration did not change the disease phenotypes in BXSB/MpJ-. At three months, both sham-operated and castrated BXSB/MpJ- manifested splenomegaly, autoantibody production, and glomerulonephritis, and castrated BXSB/MpJ- tended to show heavier spleen weights than the sham-operated group. At six months, both the treated BXSB/MpJ- showed equivalent autoimmune disease conditions; however, castrated mice clearly showed milder glomerular sclerotic lesions than the sham-operated groups. Urinary albumin excretion in castrated BXSB/MpJ- was significantly milder than in sham-operated mice at four months, but those of both the treated BXSB/MpJ- were comparable at six months. The examined renal histopathological indices in parietal epithelial cells were remarkably altered by castration. Briefly, castration decreased the height of parietal epithelial cells and total parietal epithelial cell number in BXSB/MpJ- at six months. For immunostaining, parietal epithelial cells facing the injured glomeruli of BXSB/MpJ- expressed CD44, an activated parietal epithelial cell marker, and CD44-positive parietal epithelial cells showed nuclear localization of the androgen receptor and proliferation marker Ki67. CD44- or Ki67-positive parietal epithelial cells were significantly fewer in castrated group than in sham-operated BXSB/MpJ- at six months. Further, quantitative indices for CD44-positive parietal epithelial cell number and frequency in renal corpuscles positively correlated with glomerular sclerotic severity in BXSB/MpJ-. In conclusion, androgen seemed to have an effect on both systemic immunity and renal morpho-function; however, the effect on the latter could be more clearly observed in BXSB/MpJ-, as parietal epithelial cell activation resulted in glomerular sclerosis.
性激素有助于维持哺乳动物的正常免疫和肾脏内环境稳定，其多功能特性是性别依赖性疾病发生的特征。为了阐明性激素对自身免疫性疾病相关肾发病机制的贡献，我们研究了 BXSB/MpJ-作为一种小鼠自身免疫性肾小球肾炎模型。BXSB/MpJ-及其野生型 BXSB/MpJ-在 3 周龄时被去势或假手术，并在 6 月龄时进行检查。两种去势的品系血清睾丸酮水平和体重均明显低于假手术组。去势并未改变 BXSB/MpJ-的疾病表型。在 3 个月时，假手术组和去势组的 BXSB/MpJ-均出现脾肿大、自身抗体产生和肾小球肾炎，而去势组的脾重比假手术组更重。在 6 月龄时，两种处理后的 BXSB/MpJ-的自身免疫病情况相当；然而，去势组的肾小球硬化病变明显比假手术组轻。在 4 月龄时，去势的 BXSB/MpJ-的尿白蛋白排泄明显比假手术组轻，但在 6 月龄时，两种处理后的 BXSB/MpJ-的尿白蛋白排泄相当。去势明显改变了壁层上皮细胞的肾组织病理学指标。简而言之，去势使 6 月龄 BXSB/MpJ-的壁层上皮细胞高度和壁层上皮细胞总数减少。免疫组织化学染色显示，面对 BXSB/MpJ-损伤肾小球的壁层上皮细胞表达激活的壁层上皮细胞标志物 CD44，CD44 阳性的壁层上皮细胞显示雄激素受体和增殖标志物 Ki67 的核定位。在 6 月龄时，与假手术组的 BXSB/MpJ-相比，去势组的 CD44 或 Ki67 阳性的壁层上皮细胞显著减少。此外，肾小球硬化严重程度与肾小体 CD44 阳性壁层上皮细胞数量和频率的定量指标呈正相关。总之，雄激素似乎对全身免疫和肾脏形态功能都有影响；然而，在 BXSB/MpJ-中，后者的影响更为明显，因为壁层上皮细胞的激活导致了肾小球硬化。
