Theranostics
·
2023
·
IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
研究领域:
肾病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2020
·
IF 6.205
Chao Wang,Mingrui Xiong,Chen Yang,Dong Yang,Jiaojiao Zheng,Yu Fan,Shun Wang,Yongkang Gai,Xiaoli Lan,Hong Chen,Ling Zheng,Kun Huang
Acute kidney injury (AKI), mostly caused by renal ischemia–reperfusion (I/R) injury and nephrotoxins, is characterized by rapid deterioration in renal-functions without effective drug treatment available. Through activation of a G protein-coupled receptor APJ, a furin-cleaved fragment of Elabela (ELA[22-32], E11), an endogenous APJ ligand, protects against renal I/R injury. However, the poor plasma stability and relatively weak APJ-binding ability of E11 limit its application. To address these issues, we rationally designed and synthesized a set of E11 analogues modified by palmitic acid (Pal) or polyethylene glycol; improved plasma stability and APJ-binding capacity of these analogues were achieved. In cultured renal tubular cells, these analogues protected against hypoxia-reperfusion or cisplatin-caused injury. For renal I/R-injured mice, these analogues showed improved reno-protective effects than E11; notably, Pal-E11 showed therapeutic effects at 24 h post I/R injury. These results present ELA analogues as potential therapeutic options in managing AKI.
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yun Leng,Tianyi Xie,Yufeng Tao,Yuting Zeng,Qing Zhu,Lei Wang
ELABELA (ELA), an endogenous peptide, exhibits antioxidant and anti-inflammatory properties in the heart and kidney. This study aimed to explore the therapeutic potential of ELA in hyperuricemia (HUA) and its underlying mechanism. Male C57BL/6 mice were used to induce HUA via oral administration of adenine and potassium oxonate for 14 days. 32 or 11 amino-acid ELA peptides (ELA32 or ELA11) were intraperitoneally injected into HUA mice. Compared with the HUA group, both ELA peptides significantly reduced serum UA levels, as well as hepatic expression and activity of XOD. ELA32 also decreased BUN, serum creatinine, AST, ALT and cholesterol levels while ELA11 diminished BUN and serum creatinine. Furthermore, both ELA peptides modulated bile acid (BA) synthesis, primarily through suppression of CYP27A1. Hepatic BA profiling revealed that HUA increased levels of taurochenodeoxycholic acid (TCDCA), whereas ELA treatment elevated levels of taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), and tauro-β-muricholic acid (T-βMCA). ELA32 additionally promoted accumulation of cholic acid (CA) and taurodeoxycholic acid (TDCA). In human hepatocytes HepG2, both ELA peptides reduced H 2 O 2 -induced protein levels of XOD and CYP27A1, while enhanced FXR expression. CYP27A1 deficiency mimicked the effects of ELA32 on XOD and FXR expression under H 2 O 2 stimulation. Moreover, TCA, TUDCA, TCDCA, CA and TDCA reversed H 2 O 2 -mediated regulation of XOD and FXR expression. These findings suggest that both ELA32 and ELA11 alleviate HUA in mice primarily by inhibiting XOD expression through CYP27A1-regulated BA metabolism. Our study suggests that ELA has therapeutic potential for the treatment of HUA.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）