Local cyclic adenosine monophosphate signalling cascades—Roles and targets in chronic kidney disease
Local cyclic adenosine monophosphate signalling cascades—Roles and targets in chronic kidney disease
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DOI：
10.1111/apha.13641
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发表时间：
2021-03
影响因子：
6.3
通讯作者：
Anastasiia Sholokh;E. Klussmann
中科院分区：
文献类型：
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作者：
Anastasiia Sholokh;E. Klussmann
慢性肾脏疾病(CKD)的分子机制知之甚少，治疗选择有限，这种情况支持了阐明致病分子机制和确定创新治疗选择的必要性。目前发现，环化的3‘，5’-腺苷一磷酸(CAMP)信号发生在纳米尺度内的特定细胞间隔中，其调节失调与CKD相关。CAMP的区域化受到一组特定蛋白质的严格控制，包括A-激酶锚定蛋白(AKAPs)和磷酸二酯酶(PDE)。AKAP18、AKAP220、AKAP-LBC、STUB1和PDE4等AKAP通过收集导管主细胞来协调精氨酸加压素(AVP)诱导的水重吸收。然而，AVP系统的过度激活与肾脏损害和CKD有关。足细胞损伤涉及异常的AKAP信号。免疫细胞中的cAMP信号可以是局部的，并减缓CKD典型的炎症过程的进展。慢性肾脏病的一个主要危险因素是高血压。CAMP直接从肾小球旁细胞释放血压调节剂肾素，并通过ENaC、NKCC2和NCC在肾脏对Na+的重吸收中发挥作用。CAMP降解PDE3A的突变会导致cAMP降低，从而导致高血压。慢性肾脏病的另一个主要危险因素是糖尿病。AKAP18和AKAP150以及几个PDE参与了胰岛素的释放。尽管数据越来越多，但对与慢性肾脏病相关的cAMP信号功能的了解还很零碎。功能的揭示将提高对生理过程的理解，识别与疾病相关的异常可能为CKD的治疗提供新的治疗理念。
The molecular mechanisms underlying chronic kidney disease (CKD) are poorly understood and treatment options are limited, a situation underpinning the need for elucidating the causative molecular mechanisms and for identifying innovative treatment options. It is emerging that cyclic 3′,5′‐adenosine monophosphate (cAMP) signalling occurs in defined cellular compartments within nanometre dimensions in processes whose dysregulation is associated with CKD. cAMP compartmentalization is tightly controlled by a specific set of proteins, including A‐kinase anchoring proteins (AKAPs) and phosphodiesterases (PDEs). AKAPs such as AKAP18, AKAP220, AKAP‐Lbc and STUB1, and PDE4 coordinate arginine‐vasopressin (AVP)‐induced water reabsorption by collecting duct principal cells. However, hyperactivation of the AVP system is associated with kidney damage and CKD. Podocyte injury involves aberrant AKAP signalling. cAMP signalling in immune cells can be local and slow the progression of inflammatory processes typical for CKD. A major risk factor of CKD is hypertension. cAMP directs the release of the blood pressure regulator, renin, from juxtaglomerular cells, and plays a role in Na+ reabsorption through ENaC, NKCC2 and NCC in the kidney. Mutations in the cAMP hydrolysing PDE3A that cause lowering of cAMP lead to hypertension. Another major risk factor of CKD is diabetes mellitus. AKAP18 and AKAP150 and several PDEs are involved in insulin release. Despite the increasing amount of data, an understanding of functions of compartmentalized cAMP signalling with relevance for CKD is fragmentary. Uncovering functions will improve the understanding of physiological processes and identification of disease‐relevant aberrations may guide towards new therapeutic concepts for the treatment of CKD.