Abstract: FR-PO194
Angiotensin-Converting Enzyme 2 in AKI Was Attenuated by Uremia Toxin Indoxyl Sulfate and Restored by Renin-Angiotensin-Aldosterone System Inhibitors
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Young, Guang-huar, Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Wu, Vincent, National Taiwan University Hospital, Taipei, Taiwan
Group or Team Name
- The Consortium for Acute Kidney Injury and Renal Diseases (CAKs).
Background
The accumulation of uremic toxins in patients after acute kidney injury (AKI) is harmful to long-term adverse outcome, but their effects on the severity of AKI by affecting intra-renal renin-angiotensin-aldosterone-system (RAAS) remain uncertain. Indoxyl sulfate (IS) as a representative uremic toxin, causes well-known detrimental effects during kidney injury.
Methods
Human renal proximal renal cells (HK2) were provoked with cobalt chloride to induce hypoxia injury and then supplied with indoxyl sulfate (IS) for the designated time peroids. Cell proliferation was mwasured by MTT assay and cellular ROS was evakuated by DCFDA methods. Male w/t (C57BL6) and homozygous angiotensin-converting enzyme 2 (ACE2)-knockout mice were used for animal model of AKI with uremia. Mice were randomly assigned to six groups: (1) Negative control group; (2) AKI group, unilaterial renal ischemia/reperfusion (I/R) injury to induce AKI; (3) AKI/IS group, AKI mice received IS injection; AKI/IS mice administrated with (4) direct renin inhibitor (DRI), (5) angiotensin II receptor blocker (ARB), and (6) alpha-1-adrenergic blocker, respectively.
Results
Cell study examined the expressions of ACE2 and related downstream metabolites under hypoxia/IS-induced injury. HK2 exposed to cobalt chloride/IS raised cellular oxidative stress and reduced ACE2 levels. These effects were mitigated by DRI or ARB treatment. Similarly, IS activated the ACE/angiotensin II axis of RAAS in mice after renal I/R injury and caused the reduction of ACE2 in mice kidneys. RAASi administration restored the renal ACE2 expression and Angiotensin1–7 (Ang1-7) levels and reduced neutrophil gelatinase-associated lipocalin expression and reactive oxygen species production in IS-enhanced AKI mice. Yet, these effects were absent in ACE2-knockout mice, even after RAASi therapy. Renal microcirculation analysis also showed that RAASi therapy improved the renal hypoperfusion, especially in AKI/IS mice. In hypertensive CKD patients, both DRI and ARB attenuated oxidative stress and increased serum Ang1-7 levels. ARBs, but not DRI, further restored patients’ serum ACE2 levels.
Conclusion
Our study revealed that IS enhanced the suppression of the ACE2/Ang1-7 axis in intrarenal RAAS after I/R injury, whereas RAASi restored ACE2 expression and decreased oxidative stress.
Funding
- Government Support – Non-U.S.