Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury
Background:. Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) regulate critical cell functions, including actomyosin contractility, apoptosis, and proliferation. Some studies suggest that ROCK inhibition may serve as a treatment for liver fibrosis. More investigation is needed to understand the role...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2025-02-01
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| Series: | Hepatology Communications |
| Online Access: | http://journals.lww.com/10.1097/HC9.0000000000000636 |
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| _version_ | 1832540487539490816 |
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| author | Jessica M. Herrera Yun Weng Tyler J. Lieberthal Marcus Paoletti Tammy T. Chang |
| author_facet | Jessica M. Herrera Yun Weng Tyler J. Lieberthal Marcus Paoletti Tammy T. Chang |
| author_sort | Jessica M. Herrera |
| collection | DOAJ |
| description | Background:. Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) regulate critical cell functions, including actomyosin contractility, apoptosis, and proliferation. Some studies suggest that ROCK inhibition may serve as a treatment for liver fibrosis. More investigation is needed to understand the role of hepatocyte ROCK signaling in vivo, especially in the context of profibrotic liver injury.
Methods:.
Rock1
fl/fl
, Rock2
fl/fl
, and Rock1
fl/fl
; Rock2
fl/fl
mice were given adeno-associated virus serotype 8 (AAV8)-thyroid hormone-binding globulin (TBG)-Cre to produce targeted gene deletion in hepatocytes, or given AAV8-TBG-Null to generate littermate controls (WT). Mice were then placed on a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce liver injury.
Results:. Upon DDC-induced liver injury, mice with hepatocyte-specific deletion of ROCK1 alone (R1 KO) or ROCK2 alone (R2 KO) demonstrated minimal differences compared to WT. In contrast, mice with hepatocyte-specific deletion of both ROCK1 and ROCK2 (DKO) showed pervasive early mortality, increased hepatocellular injury, and decreased hepatic function. DDC-injured DKO mice demonstrated markedly distorted liver histology characterized by large cavities in the parenchyma. RNA-seq analysis showed upregulation of cell death, inflammatory, and profibrotic pathways in DDC-injured DKO liver as compared to DDC-injured WT liver. Cdkn1a (gene encoding p21) was one of the most highly upregulated genes in the DKO liver in response to DDC-induced injury. Correspondingly, there was increased hepatocyte nuclear localization of p21 and expression of cleaved caspase-3 in DDC-injured DKO liver, consistent with the activation of p21-mediated caspase-3–dependent apoptotic cell death pathways. ROCK1/ROCK2-deficient primary hepatocytes demonstrated increased susceptibility to both caspase-3–mediated apoptosis and caspase-3–independent forms of cell death in a cell intrinsic manner.
Conclusions:. ROCK signaling plays a critical role in mediating hepatocyte cell survival pathways in response to liver injury. |
| format | Article |
| id | doaj-art-c7850a8665ec4407800789fbcbb75c0e |
| institution | Kabale University |
| issn | 2471-254X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj-art-c7850a8665ec4407800789fbcbb75c0e2025-02-05T02:11:00ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2025-02-019210.1097/HC9.0000000000000636HC90000000000000636Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injuryJessica M. Herrera0Yun Weng1Tyler J. Lieberthal2Marcus Paoletti3Tammy T. Chang4 1 Department of Surgery, University of California, San Francisco, San Francisco, California, USA 1 Department of Surgery, University of California, San Francisco, San Francisco, California, USA 1 Department of Surgery, University of California, San Francisco, San Francisco, California, USA 1 Department of Surgery, University of California, San Francisco, San Francisco, California, USA 1 Department of Surgery, University of California, San Francisco, San Francisco, California, USABackground:. Rho-associated kinases 1 and 2 (ROCK1 and ROCK2) regulate critical cell functions, including actomyosin contractility, apoptosis, and proliferation. Some studies suggest that ROCK inhibition may serve as a treatment for liver fibrosis. More investigation is needed to understand the role of hepatocyte ROCK signaling in vivo, especially in the context of profibrotic liver injury. Methods:. Rock1 fl/fl , Rock2 fl/fl , and Rock1 fl/fl ; Rock2 fl/fl mice were given adeno-associated virus serotype 8 (AAV8)-thyroid hormone-binding globulin (TBG)-Cre to produce targeted gene deletion in hepatocytes, or given AAV8-TBG-Null to generate littermate controls (WT). Mice were then placed on a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce liver injury. Results:. Upon DDC-induced liver injury, mice with hepatocyte-specific deletion of ROCK1 alone (R1 KO) or ROCK2 alone (R2 KO) demonstrated minimal differences compared to WT. In contrast, mice with hepatocyte-specific deletion of both ROCK1 and ROCK2 (DKO) showed pervasive early mortality, increased hepatocellular injury, and decreased hepatic function. DDC-injured DKO mice demonstrated markedly distorted liver histology characterized by large cavities in the parenchyma. RNA-seq analysis showed upregulation of cell death, inflammatory, and profibrotic pathways in DDC-injured DKO liver as compared to DDC-injured WT liver. Cdkn1a (gene encoding p21) was one of the most highly upregulated genes in the DKO liver in response to DDC-induced injury. Correspondingly, there was increased hepatocyte nuclear localization of p21 and expression of cleaved caspase-3 in DDC-injured DKO liver, consistent with the activation of p21-mediated caspase-3–dependent apoptotic cell death pathways. ROCK1/ROCK2-deficient primary hepatocytes demonstrated increased susceptibility to both caspase-3–mediated apoptosis and caspase-3–independent forms of cell death in a cell intrinsic manner. Conclusions:. ROCK signaling plays a critical role in mediating hepatocyte cell survival pathways in response to liver injury.http://journals.lww.com/10.1097/HC9.0000000000000636 |
| spellingShingle | Jessica M. Herrera Yun Weng Tyler J. Lieberthal Marcus Paoletti Tammy T. Chang Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury Hepatology Communications |
| title | Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury |
| title_full | Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury |
| title_fullStr | Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury |
| title_full_unstemmed | Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury |
| title_short | Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury |
| title_sort | hepatocyte rho associated kinase signaling is required for mice to survive experimental porphyria associated liver injury |
| url | http://journals.lww.com/10.1097/HC9.0000000000000636 |
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