Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury
Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury init...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.161783 |
| _version_ | 1797634400066732032 |
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| author | Anna Rinaldi Hélène Lazareth Virginie Poindessous Ivan Nemazanyy Julio L. Sampaio Daniele Malpetti Yohan Bignon Maarten Naesens Marion Rabant Dany Anglicheau Pietro E. Cippà Nicolas Pallet |
| author_facet | Anna Rinaldi Hélène Lazareth Virginie Poindessous Ivan Nemazanyy Julio L. Sampaio Daniele Malpetti Yohan Bignon Maarten Naesens Marion Rabant Dany Anglicheau Pietro E. Cippà Nicolas Pallet |
| author_sort | Anna Rinaldi |
| collection | DOAJ |
| description | Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury initiated by ischemia/reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was substantially enriched with long chain fatty acids (FAs). We identified a renal FA-related gene signature with low levels of carnitine palmitoyltransferase 2 (Cpt2) and acyl-CoA synthetase medium chain family member 5 (Acsm5) and high levels of acyl-CoA synthetase long chain family member 4 and 5 (Acsl4 and Acsl5) associated with IRI, transition to chronic injury, and established chronic kidney disease in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2–Acsl4+Acsl5+Acsm5– PTCs failing to recover from IRI as identified by single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed to CPT2 repression, which, in turn, promoted lipids’ accumulation, drove profibrogenic epithelial phenotypic changes, and activated the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation engaged an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule, sustaining the progression to chronic kidney allograft injury. |
| first_indexed | 2024-03-11T12:08:17Z |
| format | Article |
| id | doaj.art-ecf79f73ddef4ea7b0a554997b738937 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:17Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-ecf79f73ddef4ea7b0a554997b7389372023-11-07T16:24:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-09-01718Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injuryAnna RinaldiHélène LazarethVirginie PoindessousIvan NemazanyyJulio L. SampaioDaniele MalpettiYohan BignonMaarten NaesensMarion RabantDany AnglicheauPietro E. CippàNicolas PalletEnergy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury initiated by ischemia/reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was substantially enriched with long chain fatty acids (FAs). We identified a renal FA-related gene signature with low levels of carnitine palmitoyltransferase 2 (Cpt2) and acyl-CoA synthetase medium chain family member 5 (Acsm5) and high levels of acyl-CoA synthetase long chain family member 4 and 5 (Acsl4 and Acsl5) associated with IRI, transition to chronic injury, and established chronic kidney disease in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2–Acsl4+Acsl5+Acsm5– PTCs failing to recover from IRI as identified by single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed to CPT2 repression, which, in turn, promoted lipids’ accumulation, drove profibrogenic epithelial phenotypic changes, and activated the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation engaged an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule, sustaining the progression to chronic kidney allograft injury.https://doi.org/10.1172/jci.insight.161783NephrologyTransplantation |
| spellingShingle | Anna Rinaldi Hélène Lazareth Virginie Poindessous Ivan Nemazanyy Julio L. Sampaio Daniele Malpetti Yohan Bignon Maarten Naesens Marion Rabant Dany Anglicheau Pietro E. Cippà Nicolas Pallet Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury JCI Insight Nephrology Transplantation |
| title | Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| title_full | Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| title_fullStr | Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| title_full_unstemmed | Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| title_short | Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| title_sort | impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury |
| topic | Nephrology Transplantation |
| url | https://doi.org/10.1172/jci.insight.161783 |
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