Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.
Hepatic and proximal tubule angiotensinogen play distinct roles in kidney dysfunction, glomerular and tubular injury, and fibrosis progression.
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肝和近曲小管血管紧张素原在肾功能障碍、肾小球和肾小管损伤以及纤维化进展中发挥着独特的作用。
DOI：
10.1152/ajprenal.00029.2022
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Padanilam,BabuJ
中科院分区：
文献类型：
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作者：
Jang,Hee-Seong;Noh,MiRa;Plumb,Troy;Lee,Kyung;He,JohnCijiang;Ferrer,FernandoA;Padanilam,BabuJ
肾素-血管紧张素系统的组分，包括血管紧张素原（AGT），是慢性肾病（CKD）发生和进展的关键因素。然而，组织来源的AGTs在CKD中的具体作用尚未完全了解。为了确定肝脏与肾脏AGT在CKD发展中的作用，我们在野生型（WT）、近端小管（PT）或肝脏特异性AGT敲除（KO）小鼠中进行了5/6肾切除术（Nx）（一种已建立的CKD模型）。Nx显著升高WT小鼠肾内AGT表达和升高血压（BP）。在肝脏特异性AGT KO小鼠中，肾内AGT蛋白的增加被完全阻断，血压降低，这表明肝脏AGT在CKD期间的血压调节中起着至关重要的作用。与PT特异性AGT KO和WT小鼠相比，肝脏特异性AGT KO小鼠中Nx诱导的肾小球和肾脏损伤和功能障碍以及纤维化均在更大程度上减弱。然而，PT和肝脏特异性AGT KO小鼠肾脏中间质纤维化的抑制相当。我们的研究结果表明，肝脏AGT在驱动肾小球和肾小管损伤、肾功能不全和纤维化进展中起关键作用，而PT AGT的作用仅限于慢性肾功能不全的间质纤维化进展。我们的研究结果为开发组织靶向的肾素-血管紧张素系统干预治疗CKD提供了新的见解。新&值得注意的是，慢性肾脏病（CKD）是一种主要的未满足的医疗需求，没有有效的治疗方法。目前的研究结果表明，肝和近端小管血管紧张素原在慢性肾脏病发展过程中的肾小管和肾小球损伤、纤维化和肾功能障碍中具有不同的作用。由于包括血管紧张素原在内的肾素-血管紧张素系统成分是临床治疗CKD的重要靶点，因此我们的研究结果可用于开发更好的CKD和其他纤维增生性疾病的组织靶向治疗策略。
Components of the renin-angiotensin system, including angiotensinogen (AGT), are critical contributors to chronic kidney disease (CKD) development and progression. However, the specific role of tissue-derived AGTs in CKD has not been fully understood. To define the contribution of liver versus kidney AGT in the CKD development, we performed 5/6 nephrectomy (Nx), an established CKD model, in wild-type (WT), proximal tubule (PT)- or liver-specific AGT knockout (KO) mice. Nx significantly elevated intrarenal AGT expression and elevated blood pressure (BP) in WT mice. The increase of intrarenal AGT protein was completely blocked in liver-specific AGT KO mice with BP reduction, suggesting a crucial role for liver AGT in BP regulation during CKD. Nx-induced glomerular and kidney injury and dysfunction, as well as fibrosis, were all attenuated to a greater extent in liver-specific AGT KO mice compared with PT-specific AGT KO and WT mice. However, the suppression of interstitial fibrosis in PT- and liver-specific AGT KO mouse kidneys was comparable. Our findings demonstrate that liver AGT acts as a critical contributor in driving glomerular and tubular injury, renal dysfunction, and fibrosis progression, whereas the role of PT AGT was limited to interstitial fibrosis progression in chronic renal insufficiency. Our results provide new insights for the development of tissue-targeted renin-angiotensin system intervention in the treatment of CKD.NEW & NOTEWORTHYChronic kidney disease (CKD) is a major unmet medical need with no effective treatment. Current findings demonstrate that hepatic and proximal tubule angiotensinogen have distinct roles in tubular and glomerular injury, fibrogenesis, and renal dysfunction during CKD development. As renin-angiotensin system components, including angiotensinogen, are important targets for treating CKD in the clinic, the results from our study may be applied to developing better tissue-targeted treatment strategies for CKD and other fibroproliferative diseases.