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Updated: Jun 26, 2025
Bilateral Renal Ischemia-Reperfusion Model for Acute Kidney Injury in Mice
Published on: February 2, 2024
Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion
Yong Kwon Han1, Hui Jae Lim2, GiBong Jang2
1Department of Anatomy, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea.
Background:
Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle).
Methods:
Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC).
Results:
KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione β-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion.
Conclusions:
These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.
Insights
Acute kidney injury damages liver cells and their primary cilia, impairing bile secretion. Restoring glutathione and hydrogen sulfide levels may protect against this injury.
Area of Science:
- Hepatology
- Nephrology
- Cell Biology
Background:
- Acute kidney injury (AKI) frequently leads to distant liver injury, impacting patient outcomes.
- Current research on AKI-associated liver injury primarily focuses on hepatocytes, leaving cholangiocyte involvement understudied.
- Cholangiocytes, the epithelial cells lining bile ducts, possess primary cilia crucial for bile secretion.
Purpose of the Study:
- To investigate the role of cholangiocytes and their primary cilia in liver injury induced by AKI.
- To explore the impact of kidney ischemia and reperfusion (KIR) on cholangiocyte function and bile secretion.
- To assess the therapeutic potential of N-acetyl-cysteine (NAC) in mitigating AKI-induced liver injury.
Main Methods:
- Utilized wild-type and cystathione γ-lyase (CSE)-deficient mice subjected to kidney ischemia followed by reperfusion (KIR).
- Administered N-acetyl-cysteine (NAC) to some KIR-exposed mice.
- Analyzed liver tissue and bile for cellular damage, primary cilia integrity, glutathione (GSH) levels, and hydrogen sulfide (H2S) production.
Main Results:
- KIR induced damage to hepatocytes and cholangiocytes, disrupted cholangiocyte primary cilia, and impaired bile secretion.
- KIR significantly reduced hepatic GSH and H2S levels, leading to increased oxidative stress.
- NAC administration ameliorated KIR-induced liver injury by increasing GSH and H2S, while CSE deficiency worsened the injury.
Conclusions:
- Kidney ischemia and reperfusion injury causes cholangiocyte damage, primary cilia disruption, and abnormal bile secretion.
- Reduced hepatic antioxidative capacity, specifically lower GSH and H2S levels, underlies KIR-induced cholangiocyte dysfunction.
- Targeting antioxidative pathways, such as those involving CSE, may offer therapeutic strategies for AKI-associated liver injury.
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