KMUP-1通过介导NO / cGMP / PKG信号通路调节慢性肾功能衰竭中的血管钙化。,Life Sciences

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KMUP-1通过介导NO / cGMP / PKG信号通路调节慢性肾功能衰竭中的血管钙化。
Life Sciences ( IF 5.2 ) Pub Date : 2020-04-18 , DOI: 10.1016/j.lfs.2020.117683
Lian-Sheng Ren ₁ , Lei Zhang ₁ , Dan Zhu ₁ , Tong Li ₁ , Qi Wang ₁ , Xue-Ying Yuan ₁ , Li-Rong Hao ₁

Affiliation

目的通过介导NO / cGMP / PKG途径探讨KMUP-1在慢性肾功能衰竭（CRF）血管钙化中的潜在机制，为CRF治疗提供新的见解。方法采用有/无L-NNA（一种NOS抑制剂）的KMUP-1处理CRF大鼠，然后通过ELISA，茜素红染色，Von Kossa染色，Masson三色染色，Sirius红染色和CD3免疫组化染色进行处理。同时，从大鼠收集血管平滑肌细胞（VSMC），以证实KMUP-1通过NO / cGMP / PKG途径体外对血管钙化的作用。此外，分别通过蛋白质印迹和qRT-PCR确定蛋白质和mRNA表达。结果CRF大鼠24小时尿蛋白，血尿素氮（BUN），血清肌酐，Cys-C水平和炎性细胞因子升高。除了，CRF大鼠还显示出骨形成分化相关标志物的mRNA上调，从而增加了钙含量和ALP水平。此外，在CRF大鼠中还发现了eNOS和PKG的表达上调，以及NOx和cGMP的下调。然而，通过激活NO / cGMP / PKG途径进行KMUP-1治疗，可显着改善肾衰竭和CRF的血管钙化。此外，KMUP-1处理可减弱钙化的VSMC，并伴有钙化结节，钙水平和ALP活性的降低。此外，L-NNA对CRF大鼠的治疗或钙化的VSMC均可拮抗KMUP-1的改善作用。结论KMUP-1可通过激活NO / cGMP / PKG途径至少部分改善CRF大鼠的肾功能和血管钙化。

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KMUP-1 regulates the vascular calcification in chronic renal failure by mediating NO/cGMP/PKG signaling pathway.

OBJECTIVE To explore the potential mechanism of KMUP-1 in the vascular calcification of chronic renal failure (CRF) through mediating NO/cGMP/PKG pathway, and provide novel insights into the CRF treatment. METHODS CRF rats were treated by KMUP-1 with/without L-NNA (a NOS inhibitor) and then performed by ELISA, alizarin red staining, Von Kossa staining, Masson's trichrome, Sirius red staining and CD3 immunohistochemical staining. Simultaneously, vascular smooth muscle cells (VSMCs) were collected from rats to confirm the effect of KMUP-1 on vascular calcification in vitro via NO/cGMP/PKG pathway. Besides, protein and mRNA expressions were determined via Western blotting and qRT-PCR, respectively. RESULTS CRF rats were elevated in 24-h urine protein, blood urea nitrogen (BUN), serum creatinine, Cys-C levels and inflammatory cytokines. Besides, CRF rats also showed increased calcium content and ALP level with up-regulated mRNA of osteogenic differentiation-related markers. Furthermore, the up-regulated expressions of eNOS and PKG, as well as down-regulated levels of NOx and cGMP were also found in CRF rats. However, renal failure and vascular calcification of CRF were improved significantly by KMUP-1 treatment via activation of NO/cGMP/PKG pathway. Moreover, KMUP-1 treatment attenuated calcified VSMCs, accompanied by the decreases in the calcified nodules, level of calcium and activity of ALP. In addition, either L-NNA treatment for CRF rats or the calcified VSMCs could antagonize the improving effect of KMUP-1. CONCLUSION KMUP-1 can improve the renal function and vascular calcification in CRF rats at least in part by activating NO/cGMP/PKG pathway.

更新日期：2020-04-18

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