Familial hyperkalemic hypertension (FHHt; also called pseudohypoaldosteronism type II) is a hereditary hypertensive disease which can be caused by mutations in four genes: WNK1 [with no lysine (K) 1], WNK4, Kelch-like3 (KLHL3), and cullin3 (CUL3). Decreased KLHL3 expression was identified as being involved in the pathogenesis of FHHt caused by cullin 3 disease mutations. Recent studies have revealed an increased WNK4 and hence Na-Cl cotransporter (NCC) activity in the db/db mice, resulting from PKC-mediated KLHL3 phosphorylation, which impairs the degradation of its substrate, WNK4. However, whether WNK4 and NCC were activated in type 1 diabetes still remains unclear. We created streptozotocin-induced type 1 diabetic mice and revealed that renal WNK-oxidative stress response kinase-1/STE20/SPS1-related proline alanine–rich kinase (OSR1/SPAK)-NCC cascade was activated, whereas KLHL3 expression was markedly decreased and CUL3 was heavily neddylated. Moreover, decreased KLHL3 was reversed and WNK1 and WNK4 abundance increased by MLN4924, a neddylation inhibitor. In vitro, our study also showed decreased KLHL3 abundance without any significant change in phosphorylated KLHL3 under high glucose exposure. These results indicate that decreased KLHL3 likely plays a role in the pathogenesis of renal sodium reabsorption in hyperglycemic conditions.

家族性高钾性高血压（FHHt；也称为 II 型假性醛固酮增多症）是一种遗传性高血压疾病，可由四种基因突变引起： WNK1 [不含赖氨酸 (K) 1]、 WNK4 、 Kelch-like3 (KLHL3) 和cullin3 （ CUL3）。 KLHL3 表达减少被确定与 cullin 3 疾病突变引起的 FHHt 发病机制有关。最近的研究表明，db/db 小鼠中 WNK4 和 Na-Cl 协同转运蛋白 (NCC) 活性增加，这是由于 PKC 介导的 KLHL3 磷酸化造成的，这会损害其底物 WNK4 的降解。然而，WNK4 和 NCC 是否在 1 型糖尿病中被激活仍不清楚。我们创建了链脲佐菌素诱导的 1 型糖尿病小鼠，结果发现肾脏 WNK 氧化应激反应激酶 1/STE20/SPS1 相关的富含脯氨酸丙氨酸激酶 (OSR1/SPAK)-NCC 级联被激活，而 KLHL3 表达显着降低，并且CUL3 被严重neddylated。此外，neddylation 抑制剂 MLN4924 可以逆转 KLHL3 的下降，并增加 WNK1 和 WNK4 的丰度。在体外，我们的研究还显示，在高葡萄糖暴露下，KLHL3 丰度降低，但磷酸化 KLHL3 没有任何显着变化。这些结果表明 KLHL3 减少可能在高血糖条件下肾钠重吸收的发病机制中发挥作用。