Araos Patricio, León Pablo, Gallegos-Pérez Ignacio, Schäfer Carolina, García-Betancourt Richard, Salas-Huenuleo Edison, Prado Carolina, Barrientos Víctor, Liberona Jessica, Kojimahara Tomohiro, Figueroa Stefanny M, Amador Cristián A, Carreño Leandro J, Kogan Marcelo J, Gonzalez Alexis A, Pacheco Rodrigo, Alzamora Rodrigo, Brooks Heddwen L, Michea Luis
Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Am J Physiol Renal Physiol. 2025 Jul 1;329(1):F87-F98. doi: 10.1152/ajprenal.00212.2024. Epub 2025 May 6.
Antigen-presenting cells (APCs) are present in the renal interstitium and may modulate tubular function. We hypothesize that angiotensin II (Ang II) induces a prohypertensive phenotype in renal APCs, contributing to decreased natriuresis and hypertension. We evaluated the role of renal APCs as modulators of blood pressure (BP) in CD11c.DOG mice injected with diphtheria toxin (DT). Elimination of 70% of renal APCs by DT prevented the increase in BP, cardiac hypertrophy, decreased natriuresis, and sodium-potassium-chloride cotransporter type II (NKCC2) activation. Second, we compared the effect of the adoptive transfer of renal and splenic APCs on BP and natriuresis in wild-type mice. Renal APCs from Ang II mice induced a transient BP increase and reduced natriuresis. In contrast, renal APCs from control mice or splenic APCs from control or Ang II-infused mice did not modify BP or natriuresis. In CD11c.DOG mice depleted of dendritic cells (DCs), the adoptive transfer of renal APCs from Ang II-infused mice increased the BP. However, RAG1 knockout mice, devoid of T cells, did not present an increase in BP after the adoptive transfer of renal APCs of Ang II-infused mice. Renal APCs from Ang II-infused mice showed increased NOX2, SGK1, and pro-inflammatory cytokine expression compared with control renal APCs. Cell-tracking experiments of transferred renal APCs into a normotensive host showed preferential homing to the host kidneys and higher receptor expression for the renal-homing chemokine, fractalkine (CX3CR1). We conclude that renal APCs acquire a prohypertensive phenotype due to high Ang II levels, conferring the ability to modulate renal sodium handling. Ablation of APCs prevented Ang II-induced hypertension, NKCC2 activation, and preserved natriuresis. Transfer of renal APCs from Ang II-mice increased BP and reduced natriuresis in recipient mice; renal APCs from normotensive mice or splenic APCs from Ang II-infused mice had no effect. The effect of renal APCs was dependent on the presence of T cells. Renal APCs from Ang II-mice showed preferential destination to the kidney and increased expression of cytokines.
抗原呈递细胞（APCs）存在于肾间质中，并可能调节肾小管功能。我们推测血管紧张素II（Ang II）在肾APCs中诱导出一种促高血压表型，导致钠利尿减少和高血压。我们评估了肾APCs作为注射白喉毒素（DT）的CD11c.DOG小鼠血压（BP）调节因子的作用。DT消除70%的肾APCs可防止血压升高、心脏肥大、钠利尿减少以及II型钠-钾-氯共转运体（NKCC2）激活。其次，我们比较了肾和脾APCs过继转移对野生型小鼠血压和钠利尿的影响。来自Ang II小鼠的肾APCs可引起短暂的血压升高并减少钠利尿。相比之下，来自对照小鼠的肾APCs或来自对照或输注Ang II小鼠的脾APCs对血压或钠利尿没有影响。在缺乏树突状细胞（DCs）的CD11c.DOG小鼠中，输注Ang II小鼠的肾APCs过继转移会使血压升高。然而，缺乏T细胞的RAG1基因敲除小鼠在输注Ang II小鼠的肾APCs过继转移后血压并未升高。与对照肾APCs相比，输注Ang II小鼠的肾APCs显示出NOX2、SGK1和促炎细胞因子表达增加。将转移的肾APCs注入正常血压宿主的细胞追踪实验显示，它们优先归巢到宿主肾脏，并且对肾归巢趋化因子fractalkine（CX3CR1）的受体表达更高。我们得出结论，由于高Ang II水平，肾APCs获得了促高血压表型，赋予了调节肾钠处理的能力。APCs的消融可防止Ang II诱导的高血压、NKCC2激活，并保留钠利尿功能。输注Ang II小鼠的肾APCs转移可使受体小鼠血压升高并减少钠利尿；正常血压小鼠的肾APCs或输注Ang II小鼠的脾APCs则没有影响。肾APCs的作用依赖于T细胞的存在。输注Ang II小鼠的肾APCs显示出优先归巢到肾脏以及细胞因子表达增加。
