Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
Veterans Affairs Portland Health Care System, Portland, Oregon.
Am J Physiol Renal Physiol. 2022 Jul 1;323(1):F4-F19. doi: 10.1152/ajprenal.00436.2021. Epub 2022 May 9.
Cullin-RING ligases are a family of E3 ubiquitin ligases that control cellular processes through regulated degradation. Cullin 3 targets with-no-lysine kinase 4 (WNK4), a kinase that activates the Na-Cl cotransporter (NCC), the main pathway for Na reabsorption in the distal convoluted tubule (DCT). Mutations in the cullin 3 gene lead to familial hyperkalemic hypertension by increasing WNK4 abundance. The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) regulates the activity of cullin-RING ligases by removing the ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8. Genetic deletion of the catalytically active CSN subunit, , along the nephron in mice (KS-) led to increased WNK4 abundance; however, NCC abundance was substantially reduced. We hypothesized that the reduction in NCC resulted from a cortical injury that led to hypoplasia of the segment, which counteracted WNK4 activation of NCC. To test this, we studied KS- mice at weekly intervals over a period of 3 wk. The results showed that NCC abundance was unchanged until 3 wk after deletion, at which time other DCT-specific proteins were also reduced. The kidney injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin demonstrated kidney injury immediately after deletion; however, the damage was initially limited to the medulla. The injury progressed and expanded into the cortex 3 wk after deletion coinciding with loss of the DCT. The data indicate that nephron-specific disruption of the cullin-RING ligase system results in a complex progression of tubule injury that leads to hypoplasia of the DCT. Cullin 3 (CUL3) targets with-no-lysine-kinase 4 (WNK4), which activates Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney. Renal-specific genetic deletion of the constitutive photomorphogenesis 9 signalosome, an upstream regulator of CUL3, resulted in a reduction of NCC due to DCT hypoplasia, which coincided with cortical kidney injury. The data indicate that nephron-specific disruption of the cullin-RING ligase system results in a complex progression of tubule injury leading to hypoplasia of the DCT.
Cullin-RING 连接酶是 E3 泛素连接酶家族的一种，通过调节降解来控制细胞过程。Cullin 3 靶向无赖氨酸激酶 4（WNK4），WNK4 是一种激活钠-氯共转运体（NCC）的激酶，NCC 是肾脏远曲小管（DCT）中钠重吸收的主要途径。Cullin 3 基因的突变通过增加 WNK4 的丰度导致家族性高钾性高血压。组成型光形态发生 9（COP9）信号小体（CSN）通过去除泛素样蛋白神经前体细胞表达的发育下调蛋白 8 来调节 Cullin-RING 连接酶的活性。在小鼠沿肾单位的催化活性 CSN 亚基 缺失（KS-）导致 WNK4 丰度增加；然而，NCC 的丰度显著降低。我们假设 NCC 的减少是由于皮质损伤导致该段的发育不良引起的，这抵消了 WNK4 对 NCC 的激活。为了验证这一点，我们在 3 周的时间内每周对 KS-小鼠进行研究。结果表明，在删除 后的 3 周内，NCC 的丰度没有变化，此时其他 DCT 特异性蛋白也减少了。肾损伤标志物肾损伤分子-1 和中性粒细胞明胶酶相关脂质运载蛋白在 删除 后立即显示出肾脏损伤；然而，损伤最初仅限于髓质。损伤进展并扩展到皮质 3 周后 删除时，与 DCT 的丢失同时发生。数据表明，肾单位特异性 Cullin-RING 连接酶系统的破坏导致复杂的肾小管损伤进展，导致 DCT 的发育不良。Cullin 3（CUL3）靶向无赖氨酸激酶 4（WNK4），WNK4 激活肾脏远曲小管（DCT）中的钠-氯共转运体（NCC）。肾脏特异性 CUL3 上游调节因子组成型光形态发生 9 信号小体的遗传缺失导致 NCC 减少，这是由于 DCT 发育不良所致，与皮质肾损伤同时发生。数据表明，肾单位特异性 Cullin-RING 连接酶系统的破坏导致复杂的肾小管损伤进展，导致 DCT 的发育不良。
