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Role of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) and Renal Hemodynamics on Obesity Related Renal Damage

机译:N-乙酰基-丝氨酰-天冬氨酰-赖氨酰脯氨酸(Ac-SDKP)和肾脏血流动力学对肥胖相关性肾损害的作用

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摘要

Obesity is a public health problem and is associated with salt-sensitive hypertension, kidney inflammation and fibrosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a tetra-peptide with anti-inflammatory and anti-fibrotic properties but its effect on kidney damage in obesity is unknown. We hypothesized that high salt fed Zucker obese (ZO) rats develop renal damage, inflammation and fibrosis and that Ac-SDKP prevents these changes. Zucker lean (ZL) rats served as controls. Animals were treated with Ac-SDKP while maintained on either a normal-salt or HS diet for 8 weeks. Systolic blood pressure (SBP), albuminuria, renal inflammation and fibrosis were evaluated. HS diet increased macrophage infiltration in the kidneys of both ZL and ZO rats but was significantly higher in HS fed ZO rats. Ac-SDKP prevented macrophage infiltration in ZO rats. Similarly, glomerulosclerosis, cortical and medullary interstitial fibrosis were increased in ZO rats fed the HS diet, and Ac-SDKP attenuated these alterations. SBP was increased in HS-fed ZO rats, and was significantly decreased with Ac-SDKP treatment. Ac-SDKP treatment failed to improve albuminuria ZO rats. Conclusion: Ac-SDKP treatment in HS-fed ZO rats prevented renal damage by reducing inflammation, fibrosis, and SBP. Additionally, we studied the renal hemodynamics in ZO rats. ZO rats have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by the afferent arteriole (Af-Art) resistance which in turn is regulated by two intrinsic feedback mechanisms, tubuloglomerular feedback (TGF) that causes Af-Art constriction and connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in sodium chloride (NaCl) transport in the connecting tubule via the epithelial sodium channel (ENaC). Since CTGF is a dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation and decreases PGC in ZO rats. We measured stop-flow pressure (PSF), surrogate of PGC in ZO rats using in-vivo renal micropuncture. Maximal TGF response was attenuated while CTGF was elevated in ZO rats compared to ZL rats. CTGF inhibition with ENaC normalized the maximum PSF change in ZO rats indicating an important role of CTGF in TGF attenuation. Conclusion: enhanced CTGF contributes to TGF attenuation in ZO rats and potentially contributes to progressive renal damage.
机译:肥胖是一种公共卫生问题,与盐敏感性高血压,肾脏炎症和纤维化有关。 N-乙酰基-丝氨酰-天冬氨酰-赖氨酰脯氨酸(Ac-SDKP)是一种具有抗炎和抗纤维化特性的四肽,但其对肥胖中肾脏损害的作用尚不清楚。我们假设高盐喂养的祖克肥胖(ZO)大鼠会发展为肾脏损害,炎症和纤维化,而Ac-SDKP可以阻止这些变化。 Zucker lean(ZL)大鼠作为对照组。用Ac-SDKP处理动物,同时维持正常盐或HS饮食8周。评估收缩压(SBP),蛋白尿,肾脏炎症和纤维化。 HS饮食可增加ZL和ZO大鼠肾脏中的巨噬细胞浸润,但在以HS喂养的ZO大鼠中肾脏显着更高。 Ac-SDKP阻止了ZO大鼠的巨噬细胞浸润。同样,喂食HS饮食的ZO大鼠肾小球硬化,皮质和髓质间质纤维化增加,而Ac-SDKP减弱了这些改变。在HS喂养的ZO大鼠中,SBP升高,而用Ac-SDKP治疗则显着降低。 Ac-SDKP治疗未能改善蛋白尿ZO大鼠。结论:在HS喂养的ZO大鼠中,Ac-SDKP治疗可通过减少炎症,纤维化和SBP预防肾脏损害。此外,我们研究了ZO大鼠的肾脏血液动力学。 ZO大鼠的肾小球毛细血管压力(PGC)较高,可引起肾脏损害。 PGC由传入小动脉(Af-Art)阻力控制,而传入小动脉阻力又由两种内在的反馈机制调节,这两种机制分别是引起Af-Art收缩的肾小管肾小球反馈(TGF)和引起Af-Art扩张的肾小管肾小球反馈(CTGF)。通过上皮钠通道(ENaC)对连接小管中氯化钠(NaCl)转运增加的反应。由于CTGF是一种扩张机制,因此我们假设增加的CTGF有助于ZO大鼠的TGF衰减并降低PGC。我们使用体内肾脏显微穿刺技术测量了ZO大鼠的停流压力(PSF),PGC的替代物。与ZL大鼠相比,ZO大鼠的最大TGF反应减弱,而CTGF升高。 ENaC对CTGF的抑制作用使ZO大鼠的最大PSF变化正常化,表明CTGF在TGF衰减中具有重要作用。结论:增强的CTGF有助于ZO大鼠的TGF衰减,并可能导致进行性肾损伤。

著录项

  • 作者

    Maheshwari, Mani.;

  • 作者单位

    Marshall University.;

  • 授予单位 Marshall University.;
  • 学科 Pharmacology.;Physiology.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 125 p.
  • 总页数 125
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 植物学;
  • 关键词

  • 入库时间 2022-08-17 11:40:01

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