Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury
Abstract Background Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3–5-fold increase in the risk of hospital mortality compared to...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
SpringerOpen
2020-02-01
|
| Series: | Intensive Care Medicine Experimental |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40635-020-0297-3 |
| _version_ | 1818456049569497088 |
|---|---|
| author | Xiaoyan Wen Shengnan Li Alicia Frank Xiukai Chen David Emlet Neil A. Hukriede John A. Kellum |
| author_facet | Xiaoyan Wen Shengnan Li Alicia Frank Xiukai Chen David Emlet Neil A. Hukriede John A. Kellum |
| author_sort | Xiaoyan Wen |
| collection | DOAJ |
| description | Abstract Background Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3–5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease. Results Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis. Conclusions These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy. |
| first_indexed | 2024-12-14T22:20:29Z |
| format | Article |
| id | doaj.art-f6f7455ff4824854b16695b93e510f3b |
| institution | Directory Open Access Journal |
| issn | 2197-425X |
| language | English |
| last_indexed | 2024-12-14T22:20:29Z |
| publishDate | 2020-02-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Intensive Care Medicine Experimental |
| spelling | doaj.art-f6f7455ff4824854b16695b93e510f3b2022-12-21T22:45:31ZengSpringerOpenIntensive Care Medicine Experimental2197-425X2020-02-018111410.1186/s40635-020-0297-3Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injuryXiaoyan Wen0Shengnan Li1Alicia Frank2Xiukai Chen3David Emlet4Neil A. Hukriede5John A. Kellum6Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineCenter for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of MedicineAbstract Background Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3–5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease. Results Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis. Conclusions These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy.https://doi.org/10.1186/s40635-020-0297-3Acute kidney injuryRenal tissue fibrosisSepsisHistone deacetylase inhibitors |
| spellingShingle | Xiaoyan Wen Shengnan Li Alicia Frank Xiukai Chen David Emlet Neil A. Hukriede John A. Kellum Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury Intensive Care Medicine Experimental Acute kidney injury Renal tissue fibrosis Sepsis Histone deacetylase inhibitors |
| title | Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury |
| title_full | Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury |
| title_fullStr | Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury |
| title_full_unstemmed | Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury |
| title_short | Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury |
| title_sort | time dependent effects of histone deacetylase inhibition in sepsis associated acute kidney injury |
| topic | Acute kidney injury Renal tissue fibrosis Sepsis Histone deacetylase inhibitors |
| url | https://doi.org/10.1186/s40635-020-0297-3 |
| work_keys_str_mv | AT xiaoyanwen timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT shengnanli timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT aliciafrank timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT xiukaichen timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT davidemlet timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT neilahukriede timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury AT johnakellum timedependenteffectsofhistonedeacetylaseinhibitioninsepsisassociatedacutekidneyinjury |