Vasopressin Induces Urinary Uromodulin Secretion By Activating PKA (Protein Kinase A)
Vasopressin Induces Urinary Uromodulin Secretion By Activating PKA (Protein Kinase A)
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DOI：
10.1161/hypertensionaha.121.17127
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发表时间：
2021-06-01
期刊：
影响因子：
8.3
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Nanamatsu, Azuma;Mori, Takayasu;Uchida, Shinichi
尿调节素由肾小管细胞分泌，可预防尿路感染和肾结石。相反，尿调节素的细胞内积累与高血压和慢性肾病相关。然而，尿调节蛋白分泌的生理刺激仍然很大程度上未知。在这里，我们发现去氨加压素（一种加压素 2 型受体激动剂）可显着增加小鼠短期肾小管尿调节素的分泌。免疫荧光研究和基于超速离心的聚合测定表明，去氨加压素诱导尿调节素的管腔内聚合丝，表明其具有生理功能性分泌。由于排泄增加，去氨加压素明显降低了小鼠肾脏中的尿调节素丰度。我们研究了稳定表达尿调节素的肾上皮细胞，以阐明其分子机制。顶端尿调节素分泌明显增加以响应加压素/cAMP信号传导，这与体内实验一致。我们还证明，该反应依赖于上皮细胞极性和环 AMP 依赖性 PKA（蛋白激酶 A）信号通路。建议涉及 cAMP 介导的蛋白酶激活。相反，尿调节素的基底外侧分泌不依赖于cAMP信号传导。我们的工作揭示了加压素/cAMP/PKA 信号传导是尿调节蛋白分泌的生理刺激。这一发现可能为尿路感染、肾结石以及潜在的高血压和慢性肾脏病的新治疗策略提供基础。
Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown. Here, we showed that desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. We investigated kidney epithelial cells stably expressing uromodulin to clarify the molecular mechanism. Apical uromodulin secretion was clearly increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on epithelial cell polarity and cyclic AMP-dependent PKA (protein kinase A) signaling pathway. cAMP-mediated activation of proteases was suggested to be involved. In contrast, basolateral secretion of uromodulin was independent of cAMP signaling. Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for urinary tract infections, kidney stones, and potentially hypertension and chronic kidney disease.