557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis.
OBJECTIVES/GOALS: Renal fibrosis is a critical pathophysiological event in chronic kidney diseases. Our goal is to determine the ability of dual-inhibitor of transforming growth factor beta receptor 1 (TGFα²R1) and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), TK850, on reducing...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Cambridge University Press
2024-04-01
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| Series: | Journal of Clinical and Translational Science |
| Online Access: | https://www.cambridge.org/core/product/identifier/S2059866124004746/type/journal_article |
| _version_ | 1797226928122363904 |
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| author | Henry Anthony Palfrey Samaneh Goorani Amod Sharma Baku Acharya Brendan Frett John D. Imig |
| author_facet | Henry Anthony Palfrey Samaneh Goorani Amod Sharma Baku Acharya Brendan Frett John D. Imig |
| author_sort | Henry Anthony Palfrey |
| collection | DOAJ |
| description | OBJECTIVES/GOALS: Renal fibrosis is a critical pathophysiological event in chronic kidney diseases. Our goal is to determine the ability of dual-inhibitor of transforming growth factor beta receptor 1 (TGFα²R1) and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), TK850, on reducing kidney fibrosis. METHODS/STUDY POPULATION: To test the renal anti-fibrotic action ofdual TK850,8-10-week-old male and female C57BL/6mice with unilateral ureteral obstruction (UUO) induced kidney fibrosis were used. Mice were separated into 3 groups: group 1 contained mice that had UUO surgery (UUO control), group 2 contained mice prophylactically treated with TK850 thatstarted 7 days prior to UUO(UUO-P,20 mpk/d/ip), and group 3 contained mice interventionally treated with TK850 that started3 days after UUO(UUO-I,20 mpk/d/ip). Ten days following UUO the kidneys and blood were collected for analysis. Renal fibrosis was assessed from hydroxyproline content (measure of collagen)and histological collagen analysis using Picrosirius red stain. RESULTS/ANTICIPATED RESULTS: Renal hydroxyproline was increased equally in the UUO kidney of male (5.4 ± 0.41 µg/10mg, n=5) and female mice (5.5 ± 0.50 µg/10mg, n=5) compared to the contralateral control kidney (2.9 ± 0.14 µg/10mg, n=10). TK850 treatment in UUO-P mice (n=10, 3.4 ± 0.24 µg/10mg) and UUO-I mice (4.30 ± 0.20 µg/10mg, n=10) had significantly reduced hydroxyproline levels. Histopathological evaluation revealed that kidney injury increased collagen deposition in the UUO kidney (17.1 ± 0.43% collagen positive area, n=10) compared to the control kidney (2.0 ± 0.23%, n=10). TK850 treatment in UUO-P mice significantly attenuated collagen deposition (10.5 ± 0.38%, n=10), while UUO-I had significantly reduced collagen deposition as well (13.1 ± 0.25%, n=10). DISCUSSION/SIGNIFICANCE: Taken together, these results validate the dual TGFβR1/MAP4K4 inhibitor, TK850 as a potential therapeutic to mitigate renal fibrosis and supports the emergence of a combinational pharmacotherapeutic approach for multi-factorial kidney diseases. |
| first_indexed | 2024-04-24T14:32:42Z |
| format | Article |
| id | doaj.art-296d9a77d5564ee4aca3cf447f629771 |
| institution | Directory Open Access Journal |
| issn | 2059-8661 |
| language | English |
| last_indexed | 2024-04-24T14:32:42Z |
| publishDate | 2024-04-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj.art-296d9a77d5564ee4aca3cf447f6297712024-04-03T02:00:11ZengCambridge University PressJournal of Clinical and Translational Science2059-86612024-04-01816616610.1017/cts.2024.474557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis.Henry Anthony Palfrey0Samaneh Goorani1Amod Sharma2Baku Acharya3Brendan Frett4John D. Imig5University of Arkansas for Medical SciencesUniversity of Arkansas for Medical SciencesUniversity of Arkansas for Medical SciencesUniversity of Arkansas for Medical SciencesUniversity of Arkansas for Medical SciencesUniversity of Arkansas for Medical SciencesOBJECTIVES/GOALS: Renal fibrosis is a critical pathophysiological event in chronic kidney diseases. Our goal is to determine the ability of dual-inhibitor of transforming growth factor beta receptor 1 (TGFα²R1) and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), TK850, on reducing kidney fibrosis. METHODS/STUDY POPULATION: To test the renal anti-fibrotic action ofdual TK850,8-10-week-old male and female C57BL/6mice with unilateral ureteral obstruction (UUO) induced kidney fibrosis were used. Mice were separated into 3 groups: group 1 contained mice that had UUO surgery (UUO control), group 2 contained mice prophylactically treated with TK850 thatstarted 7 days prior to UUO(UUO-P,20 mpk/d/ip), and group 3 contained mice interventionally treated with TK850 that started3 days after UUO(UUO-I,20 mpk/d/ip). Ten days following UUO the kidneys and blood were collected for analysis. Renal fibrosis was assessed from hydroxyproline content (measure of collagen)and histological collagen analysis using Picrosirius red stain. RESULTS/ANTICIPATED RESULTS: Renal hydroxyproline was increased equally in the UUO kidney of male (5.4 ± 0.41 µg/10mg, n=5) and female mice (5.5 ± 0.50 µg/10mg, n=5) compared to the contralateral control kidney (2.9 ± 0.14 µg/10mg, n=10). TK850 treatment in UUO-P mice (n=10, 3.4 ± 0.24 µg/10mg) and UUO-I mice (4.30 ± 0.20 µg/10mg, n=10) had significantly reduced hydroxyproline levels. Histopathological evaluation revealed that kidney injury increased collagen deposition in the UUO kidney (17.1 ± 0.43% collagen positive area, n=10) compared to the control kidney (2.0 ± 0.23%, n=10). TK850 treatment in UUO-P mice significantly attenuated collagen deposition (10.5 ± 0.38%, n=10), while UUO-I had significantly reduced collagen deposition as well (13.1 ± 0.25%, n=10). DISCUSSION/SIGNIFICANCE: Taken together, these results validate the dual TGFβR1/MAP4K4 inhibitor, TK850 as a potential therapeutic to mitigate renal fibrosis and supports the emergence of a combinational pharmacotherapeutic approach for multi-factorial kidney diseases.https://www.cambridge.org/core/product/identifier/S2059866124004746/type/journal_article |
| spellingShingle | Henry Anthony Palfrey Samaneh Goorani Amod Sharma Baku Acharya Brendan Frett John D. Imig 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. Journal of Clinical and Translational Science |
| title | 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. |
| title_full | 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. |
| title_fullStr | 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. |
| title_full_unstemmed | 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. |
| title_short | 557 Dual TGFβR1/MAP4K4 inhibitor reduces kidney injury in a mouse model of renal fibrosis. |
| title_sort | 557 dual tgfβr1 map4k4 inhibitor reduces kidney injury in a mouse model of renal fibrosis |
| url | https://www.cambridge.org/core/product/identifier/S2059866124004746/type/journal_article |
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