Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226-0509, USA.
Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
Curr Hypertens Rep. 2020 Aug 27;22(9):61. doi: 10.1007/s11906-020-01076-8.
The goal of this review is to evaluate recent advances in understanding the pivotal roles of Cullin-3 (CUL3) in blood pressure regulation with a focus on its actions in the kidney and blood vessels.
Cul3-based ubiquitin ligase regulates renal electrolyte transport, vascular tone, and redox homeostasis by facilitating the normal turnover of (1) with-no-lysine kinases in the distal nephron, (2) RhoA and phosphodiesterase 5 in the vascular smooth muscle, and (3) nuclear factor E2-related factor 2 in antioxidant responses. CUL3 mutations identified in familial hyperkalemic hypertension (FHHt) yield a mutant protein lacking exon 9 (CUL3∆9) which displays dual gain and loss of function. CUL3∆9 acts in a dominant manner to impair CUL3-mediated substrate ubiquitylation and degradation. The consequent accumulation of substrates and overactivation of downstream signaling cause FHHt through increased sodium reabsorption, enhanced vasoconstriction, and decreased vasodilation. CUL3 ubiquitin ligase maintains normal cardiovascular and renal physiology through posttranslational modification of key substrates which regulate blood pressure. Interference with CUL3 disturbs these key downstream pathways. Further understanding the spatial and temporal specificity of how CUL3 functions in these pathways is necessary to identify novel therapeutic targets for hypertension.
本综述旨在评估 Cullin-3（CUL3）在血压调节中关键作用的最新研究进展，重点关注其在肾脏和血管中的作用。
基于 Cul3 的泛素连接酶通过促进（1）远曲小管中的无赖氨酸激酶、（2）血管平滑肌中的 RhoA 和磷酸二酯酶 5 以及（3）抗氧化反应中的核因子 E2 相关因子 2 的正常周转，调节肾脏电解质转运、血管张力和氧化还原稳态。在家族性高钾血症性高血压（FHHt）中鉴定的 CUL3 突变产生缺乏外显子 9 的突变蛋白（CUL3∆9），其表现出双重获得和丧失功能。CUL3∆9 以显性方式作用，损害 CUL3 介导的底物泛素化和降解。由此导致的底物积累和下游信号的过度激活导致 FHHt 通过增加钠重吸收、增强血管收缩和减少血管舒张。CUL3 泛素连接酶通过对调节血压的关键底物进行翻译后修饰来维持正常的心血管和肾脏生理学。干扰 CUL3 会扰乱这些关键下游途径。进一步了解 CUL3 在这些途径中发挥作用的时空特异性对于确定高血压的新治疗靶点是必要的。
