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J. Am. Soc. Nephrol., Feb 28 2025, | https://doi.org/10.1681/ASN.0000000649
p21-Activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans
Yu, Hwang Chan1; Chung, Byeoung Hoon2; Kim, Yoejin1; Lee, Yoonji3; Sim, Hyunchae4; Lee, Sangkyu4; Hwang, Hong Pil2; Yu, Hee Chul2; Jeon, Seunggyu5; Maeng, Han-Joo5; Shin, Dongyun5; Kang, Kyung Pyo6; Seo, Seung-Yong5,a; Bae, Eun Ju7; Park, Byung-Hyun1,a
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejon 34141, Republic of Korea
2Department of Surgery, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
3College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
4School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
5College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
6Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
7School of Pharmacy, Jeonbuk National University, Jeonju 54896, Republic of Korea
aCorresponding authors: Dr. Seung-Yong Seo; Prof. Byung-Hyun Park
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejon 34141, Republic of Korea
2Department of Surgery, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
3College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
4School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
5College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
6Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea
7School of Pharmacy, Jeonbuk National University, Jeonju 54896, Republic of Korea
aCorresponding authors: Dr. Seung-Yong Seo; Prof. Byung-Hyun Park
Abstract
Background: Acute kidney injury following ischemia-reperfusion remains a substantial perioperative challenge lacking effective treatment. p21-activated kinase 4 (PAK4), a downstream effector of Rho GTPase, has been explored in hepatic ischemia-reperfusion injury, but its role in renal ischemia-reperfusion is unknown.
Methods: Wild-type and proximal tubule-specific Pak4 knockout mice underwent 25 min of ischemia followed by 24 h of reperfusion injury. Primary tubular cells and HK-2 cells were exposed to hypoxia-reoxygenation injury to investigate the in vitro impact of PAK4. Selective degradation of PAK4 was employed using proteolysis-targeting chimeras (PROTAC) to ameliorate acute kidney injury.
Results: Post-ischemia-reperfusion, the expression of PAK4 was upregulated through hypoxia-inducible factor 1 alpha in mouse kidneys. Deletion of PAK4 in proximal tubule cells, but not in myeloid cells, significantly mitigated ischemia-reperfusion-induced acute kidney injury, as evidenced by decreased levels of blood urea nitrogen, creatinine, tubular necrosis, apoptosis, macrophage infiltration, and lipid accumulation compared to control mice. Further investigation revealed that PAK4 phosphorylated glutathione peroxidase 3 at T47, leading to its proteasomal degradation. Additionally, pretreatment of mice with the PAK4 PROTAC preserved glutathione peroxidase 3 and enhanced fatty acid β-oxidation, thereby protecting against acute kidney injury. In kidney tissues from people with a kidney transplant, elevated levels of PAK4 protein and phosphorylation of glutathione peroxidase 3 at T47 were observed.
Conclusions: Renal tubular PAK4 contributes to tissue damage during ischemia-reperfusion injury, while PAK4 PROTAC mitigates ischemia-reperfusion injury by reducing oxidative stress and promoting fatty acid β-oxidation.
Methods: Wild-type and proximal tubule-specific Pak4 knockout mice underwent 25 min of ischemia followed by 24 h of reperfusion injury. Primary tubular cells and HK-2 cells were exposed to hypoxia-reoxygenation injury to investigate the in vitro impact of PAK4. Selective degradation of PAK4 was employed using proteolysis-targeting chimeras (PROTAC) to ameliorate acute kidney injury.
Results: Post-ischemia-reperfusion, the expression of PAK4 was upregulated through hypoxia-inducible factor 1 alpha in mouse kidneys. Deletion of PAK4 in proximal tubule cells, but not in myeloid cells, significantly mitigated ischemia-reperfusion-induced acute kidney injury, as evidenced by decreased levels of blood urea nitrogen, creatinine, tubular necrosis, apoptosis, macrophage infiltration, and lipid accumulation compared to control mice. Further investigation revealed that PAK4 phosphorylated glutathione peroxidase 3 at T47, leading to its proteasomal degradation. Additionally, pretreatment of mice with the PAK4 PROTAC preserved glutathione peroxidase 3 and enhanced fatty acid β-oxidation, thereby protecting against acute kidney injury. In kidney tissues from people with a kidney transplant, elevated levels of PAK4 protein and phosphorylation of glutathione peroxidase 3 at T47 were observed.
Conclusions: Renal tubular PAK4 contributes to tissue damage during ischemia-reperfusion injury, while PAK4 PROTAC mitigates ischemia-reperfusion injury by reducing oxidative stress and promoting fatty acid β-oxidation.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-03-04)
- 국내 연구진
- 의약학 > 분자세포의학
관련 웨비나
![급성 신부전에서의 PAK4의 역할 [J. Am. Soc. Nephrol.]](/upload/board/files/onseminar/thumb/thumb_0000920.png)
학술웨비나
급성 신부전에서의 PAK4의 역할 [J. Am. Soc. Nephrol.] PAK4는 발암유전자로 알려져 있지만, 저희 연구실에서는 암과는 별개로 정상 조직에서의 PAK4 역할을 연구하고 있습니다. 3년 전, Hepatic I/R 상황에서 PAK4가 증가하는 것을 확인한 바 있으며, 이번 연구에서도 급성 신부전에서 PAK4가 상당히 많이 증가한다는 사실을 발견했습니다. 특히, Kidney I/R 및 급성 신부전에서의 PAK4 작용이 Hepatic I/R과 사뭇 다르게 나타난 점이 인상적이었습니다. 이번 연구에서 GPx3를 Kidney에서 새롭게 발견한 PAK4의 기질로 확인하였습니다. GPx3는 원래 항염증 및 항산화 기능을 하는 soluble protein인데, PAK4가 증가할 경우 GPx3가 분해(degradation)되고, exosome을 통한 이동도 방해받는 것으로 나타났습니다. 그러나 GPx3의 phosphorylation을 막은 mutant 형태는 PAK4에 의해 분해되지 않고, Kidney의 여러 부위로 이동하여 항산화 기능을 유지할 수 있었습니다. 마지막으로, PAK4와 GPx3 phosphorylation 사이의 양의 상관관계를 휴먼 샘플에서도 확인하며 연구를 마무리하였습니다.- 유황찬(KAIST GSMSE)
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