Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
Physiol Rep. 2020 Mar;8(6):e14401. doi: 10.14814/phy2.14401.
Renal scarring after pyelonephritis is linked to long-term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti-androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post-infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)-like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non-androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC-like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.
肾盂肾炎后肾瘢痕与高血压和慢性肾脏病的长期健康风险有关。雄激素暴露会增加雄性和雌性小鼠对尿路致病性大肠杆菌（UPEC）肾盂肾炎和由此产生的瘢痕的易感性和严重程度，而抗雄激素治疗可预防这些模型中严重的尿路感染（UTI）。本研究采用雄激素化雌性 C57BL/6 小鼠阐明了感染后肾纤维化的分子机制，并确定了这些途径如何因雄激素的存在而改变。我们发现，循环睾丸酮水平升高通过在 UTI 发作前增加局部 TGFβ1 的产生，从而为纤维化做好准备，改变转录因子 Smad2 和 Smad3 的比例，并增加间充质干细胞（MSC）样细胞和 Gli1+激活的肌成纤维细胞的存在，这些细胞主要负责瘢痕成分的沉积。在雄激素存在的情况下，TGFβ1 的产生增加和 Smad2:Smad3 的异常情况在整个感染过程中都得到维持，与非雄激素化雌性小鼠中未观察到的肾瘢痕形成相关。TGFβ1 信号通路的药理学抑制作用削弱了肌成纤维细胞的激活。我们得出结论，肾盂肾炎后肾纤维化因雄激素的存在而加剧，涉及 TGFβ1 信号级联的激活，导致皮质区 MSC 样细胞和Gli1+激活的肌成纤维细胞增加，这些细胞是瘢痕形成的原因。
