Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India.
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333031, India.
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166532. doi: 10.1016/j.bbadis.2022.166532. Epub 2022 Aug 28.
Acute kidney injury (AKI) is a collection of clinical syndromes with persistent increases in morbidity and mortality rates. Hyperglycemia is a risk factor for AKI development. Renin-angiotensin-aldosterone system (RAS) disequilibrium and Klotho downregulation also play a pivotal role in the pathogenesis of AKI. Moreover, the relationship between Klotho and ACE2 (a component of non-conventional RAS) regulation in AKI remains an unexplored area of research. Hence, in this study, we investigated ACE2 and Klotho regulation in AKI using ischemic Wistar rats and NRK52E cells under normal and hyperglycemic conditions. Our findings suggested that hyperglycemia exacerbates renal ischemia-reperfusion injury (IRI)/hypoxia-reperfusion injury (HRI) induced AKI. Systemic and renal Klotho deficiency is a novel hallmark of AKI. Additionally, ACE2 is a protective component of the RAS, and its inhibition/deficiency leads to inflammation, apoptosis, Klotho downregulation, and thus AKI development. However, ACE2 activation resulted in the amelioration of AKI. Importantly, ACE2 plays an important role in Klotho upregulation, which might act as an intermediate for ACE2-mediated reno-protection. In conclusion, ACE2 activator i.e. DIZE restored endogenous ACE2-Ang-(1-7)-Klotho level, inhibited apoptosis and inflammation, and ameliorates IRI/HRI induced AKI under diabetic and non-diabetic conditions. Hence, in future, targeting ACE2-Ang-(1-7)-Klotho axis may prove a novel therapeutic strategy against AKI, where further preclinical and clinical investigations are required to verify the clinical potential of this finding.
急性肾损伤（AKI）是一组具有持续增高发病率和死亡率的临床综合征。高血糖是 AKI 发展的危险因素。肾素-血管紧张素-醛固酮系统（RAS）失衡和 Klotho 下调在 AKI 的发病机制中也起着关键作用。此外，Klotho 与 ACE2（非传统 RAS 的一个组成部分）在 AKI 中的调节之间的关系仍然是一个未被探索的研究领域。因此，在这项研究中，我们使用缺血性 Wistar 大鼠和 NRK52E 细胞在正常和高血糖条件下研究了 AKI 中 ACE2 和 Klotho 的调节。我们的研究结果表明，高血糖加重了肾缺血再灌注损伤（IRI）/缺氧再灌注损伤（HRI）引起的 AKI。全身和肾脏 Klotho 缺乏是 AKI 的一个新特征。此外，ACE2 是 RAS 的一种保护成分，其抑制/缺乏会导致炎症、细胞凋亡、Klotho 下调，从而导致 AKI 的发生。然而，ACE2 的激活导致 AKI 的改善。重要的是，ACE2 在 Klotho 的上调中起着重要作用，这可能是 ACE2 介导的肾保护的中间环节。总之，ACE2 激活剂即 DIZE 恢复了内源性 ACE2-Ang-(1-7)-Klotho 水平，抑制了细胞凋亡和炎症，改善了糖尿病和非糖尿病条件下 IRI/HRI 引起的 AKI。因此，在未来，针对 ACE2-Ang-(1-7)-Klotho 轴可能是一种针对 AKI 的新的治疗策略，需要进一步的临床前和临床研究来验证这一发现的临床潜力。
