Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, France (B.B., S.E.M., K.U., L.L., M.S., F.J.).
Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain (N.L.-A.).
Hypertension. 2023 Sep;80(9):1860-1870. doi: 10.1161/HYPERTENSIONAHA.123.21156. Epub 2023 Jun 28.
The expression of NGAL/lcn2 (neutrophil gelatinase-associated lipocalin) is directly modulated by mineralocorticoid receptor activation but its role in blood pressure control is unclear.
a potential relationship between NGAL plasma levels, systolic blood pressure and urinary Na excretion was assessed in the STANISLAS cohort. The specific role of NGAL/lcn2 in salt-sensitive hypertension was studied using lcn2-knockout mice (lcn2 KO) fed with low-Na diet (0Na).
we show that NGAL plasma levels positively correlate with systolic blood pressure, whereas they negatively correlate with urinary Na excretion in subjects of the STANISLAS cohort. Prolonged feeding of lcn2 KO mice with a 0Na diet induced lower systolic blood pressure than that of the control group (wildtype), suggesting a role for NGAL/lcn2 in Na-balance homeostasis. Short-term or prolonged 0Na increased Na-Cl cotransporter (NCC) phosphorylation in the cortex of wildtype mice, which was prevented in lcn2 KO mice. Recombinant mouse lcn2 injections in lcn2 KO mice induced NCC phosphorylation in the kidney cortex, associated with decreased urinary Na excretion. Ex vivo experiments using kidney slices from lcn2 KO mice showed increased NCC phosphorylation by recombinant murine lcn2. In addition, recombinant murine lcn2 induced activation of CamK2β (calcium/calmodulin-dependent protein kinase II β subunit) phosphorylation in lcn2 KO mice and in kidney slices, providing an underlying mechanism involved in lcn2-induced NCC phosphorylation. Indeed, the inhibition of CamK2β prevented NCC phosphorylation induced by recombinant lcn2 in kidney slices.
we highlight a novel role of NGAL/lcn2 as a modulator of the activity of the renal sodium transporter NCC affecting salt-sensitive blood pressure.
NGAL/lcn2（中性粒细胞明胶酶相关脂质运载蛋白）的表达受盐皮质激素受体激活的直接调节，但它在血压控制中的作用尚不清楚。
在 STANISLAS 队列中评估了 NGAL 血浆水平、收缩压和尿钠排泄之间的潜在关系。使用 lcn2 敲除小鼠（lcn2 KO）在低钠饮食（0Na）下研究了 NGAL/lcn2 在盐敏感型高血压中的作用。
我们发现，STANISLAS 队列中 NGAL 血浆水平与收缩压呈正相关，而与尿钠排泄呈负相关。与对照组（野生型）相比，长期给予 lcn2 KO 小鼠 0Na 饮食会导致收缩压降低，表明 NGAL/lcn2 在钠平衡稳态中起作用。短期或长期给予 0Na 饮食会增加野生型小鼠皮质中的 Na-Cl 共转运蛋白（NCC）磷酸化，而 lcn2 KO 小鼠则不会。重组鼠 lcn2 注射到 lcn2 KO 小鼠中会诱导肾脏皮质 NCC 磷酸化，导致尿钠排泄减少。使用 lcn2 KO 小鼠的肾切片进行的离体实验表明，重组鼠 lcn2 增加了 NCC 的磷酸化。此外，重组鼠 lcn2 诱导 lcn2 KO 小鼠和肾切片中 CamK2β（钙/钙调蛋白依赖性蛋白激酶 IIβ 亚基）磷酸化的激活，为 lcn2 诱导的 NCC 磷酸化提供了潜在的机制。事实上，CamK2β 的抑制可阻止重组 lcn2 在肾切片中诱导的 NCC 磷酸化。
我们强调了 NGAL/lcn2 作为肾脏钠转运蛋白 NCC 活性调节剂的新作用，该作用影响盐敏感型血压。
