Roncal-Jimenez Carlos A, Milagres Tamara, Andres-Hernando Ana, Kuwabara Masanari, Jensen Thomas, Song Zhilin, Bjornstad Petter, Garcia Gabriela E, Sato Yuka, Sanchez-Lozada Laura G, Lanaspa Miguel A, Johnson Richard J
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado.
Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Aurora, Colorado.
Am J Physiol Renal Physiol. 2017 Mar 1;312(3):F418-F426. doi: 10.1152/ajprenal.00495.2016. Epub 2016 Dec 21.
Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V receptor-dependent pathway.
最近实验表明，反复热应激和脱水会导致慢性肾脏病（CKD）。一种潜在的介质可能是血管加压素，它通过2型血管加压素受体（V受体）发挥作用。我们检验了以下假设：去氨加压素会加速热应激和反复脱水小鼠的慢性肾脏病进程。在5周的时间里，对雄性小鼠进行反复的热暴露并限制其饮水，一组小鼠每天接受两次去氨加压素，另一组小鼠接受赋形剂。另外两个对照组未接受热暴露或脱水，分别接受赋形剂或去氨加压素。评估了治疗对肾损伤的影响。热应激和反复脱水导致了功能改变（蛋白尿、尿中性粒细胞明胶酶相关蛋白升高）、肾小球改变（系膜溶解、基质扩张）以及肾小管间质改变（纤维化、炎症）。去氨加压素在正常动物中也会导致蛋白尿、肾小球改变和肾小管间质纤维化，并且还会加重热应激肾病小鼠的损伤。热应激和/或去氨加压素还与肾皮质多元醇途径的激活有关，这可能是由于间质渗透压升高所致。我们的研究记录了热应激肾病中的肾小球和肾小管间质损伤及炎症，这可能与中美洲肾病的发病机制在临床上相关。我们的数据还表明，血管加压素可能在热应激肾病肾损伤的发病机制中起作用，可能是通过V受体依赖性途径。
