Adenine acts in the kidney as a signaling factor and causes salt- and water-losing nephropathy: early mechanism of adenine-induced renal injury
Adenine acts in the kidney as a signaling factor and causes salt- and water-losing nephropathy: early mechanism of adenine-induced renal injury
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DOI：
10.1152/ajprenal.00142.2018
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发表时间：
2019-04-01
影响因子：
4.2
通讯作者：
Amlal, Hassane
中科院分区：
文献类型：
--
作者：
Dos Santos, Ingrid F.;Sheriff, Sulaiman;Amlal, Hassane
慢性腺嘌呤喂养广泛用于开发慢性肾衰竭的动物模型，其代谢特征与人类观察到的相似。然而，人们对腺嘌呤引起肾衰竭的机制知之甚少。在这项研究中，我们检查了腺嘌呤对大鼠水代谢和盐平衡的早期影响，这些大鼠被放置在代谢笼中并喂食对照或含腺嘌呤饮食 7 天。分子和功能研究表明，腺嘌呤喂养的大鼠表现出食物摄入量显着减少、多尿、烦渴、尿渗透压降低和盐消耗增加。这些影响与食物摄入量的变化无关，是由集合管和髓质厚升肢中的水通道水通道蛋白-2 (AQP2) 和盐转运蛋白 (Na+ -K+ -Cl- 协同转运蛋白 2; NKCC2) 协调下调所致。结果，腺嘌呤喂养的大鼠表现出大量的容量消耗，表现为体重显着减轻、血液尿素氮增加、血细胞比容和血红蛋白水平增加，所有这些都通过补充 NaCl 得到显着纠正。腺嘌呤引起的尿液浓缩缺陷不能通过外源性精氨酸加压素（AVP）纠正，并且与体内和体外cAMP产生减少相关。总之，腺嘌呤作为信号分子作用于肾小管，至少通过直接干扰 AVP V2 受体信号传导以及随后肾脏中 NKCC2 和 AQP2 的下调，导致肾性尿崩症和盐消耗。肾液丢失和食物摄入减少以及随后的大量容量消耗相结合，可能在早期肾前性衰竭的发展中发挥重要作用，而在长期腺嘌呤喂养中，肾前性衰竭会进展为慢性肾脏疾病。
Chronic adenine feeding is extensively used to develop animal models of chronic renal failure with metabolic features resembling those observed in humans. However, the mechanism by which adenine induces renal failure is poorly understood. In this study, we examined the early effects of adenine on water metabolism and salt balance in rats placed in metabolic cages and fed control or adenine-containing diets for 7 days. Molecular and functional studies demonstrated that adenine-fed rats exhibited a significant reduction in food intake, polyuria, polydipsia, decreased urine osmolality, and increased salt wasting. These effects are independent of changes in food intake and result from a coordinated downregulation of water channel aquaporin-2 (AQP2) and salt transporter (Na+ -K+ -Cl- cotransporter 2; NKCC2) in the collecting duct and medullary thick ascending limb, respectively. As a result, adenine-fed rats exhibited massive volume depletion, as indicated by a significant body weight loss, increased blood urea nitrogen, and increased hematocrit and hemoglobin levels, all of which were significantly corrected with NaCl replacement. Adenine-induced urinary concentrating defect was not corrected by exogenous arginine vasopressin (AVP), and it correlated with reduced cAMP production in vivo and in vitro. In conclusion, adenine acts on renal tubules as a signaling molecule and causes nephrogenic diabetes insipidus with salt wasting, at least, by directly interfering with AVP V2 receptor signaling with subsequent downregulation of NKCC2 and AQP2 in the kidney. The combination of renal fluid loss and decreased food intake with subsequent massive volume depletion likely plays an important role in the development of early prerenal failure that progresses to chronic kidney disease in long-term adenine feeding.