Uhlean, R. | Search bioRxiv

bioRxiv2026

Proteomic Evaluation of the Progression from Acute Kidney Injury to Chronic Kidney Disease

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes with substantial global burden, yet the molecular mechanisms driving the transition from acute injury to chronic fibrosis remain incompletely understood. We performed quantitative data-independent acquisition mass spectrometry (DIA-MS) proteomics on mouse models of AKI (ischemia-reperfusion injury) and CKD (unilateral ureteral obstruction), quantifying 5,985 protein groups. A conserved core injury response of 1,475 shared proteins (46%) was dominated by mitochondrial dysfunction, loss of solute transporters, and immune and extracellular matrix remodeling. AKI was marked by chromatin reorganization, DNA damage response, and acute inflammation, whereas CKD showed sustained fibrosis, complement activation, and coagulation. Peroxisomal proteins, including the {beta}-oxidation enzymes Acox1 and Ehhadh, were consistently down-regulated in both AKI and CKD, with no peroxisomal protein up-regulated. Both models also displayed a senescence-associated secretory phenotype (SASP)-like signature, including Havcr1, Spp1, Igfbp7, Plau, and lysosomal cathepsins. We further identified 95 candidate progression markers, including Brat1 and Col3a1, 93 proteins with greater loss in CKD, 14 proteins changing in opposite directions, and seven disease-associated co-expression modules. These findings provide a proteomics resource for biomarker discovery and therapeutic targeting, including peroxisomal restoration and senolytic strategies, in AKI and CKD.

biochemistry↗

bioRxiv2023

Dicarboxylic acid supplementation protects from acute kidney injury via stimulation of renal peroxisomal activity

IntroductionLysine succinylation is a post-translational modification associated with the control of several diseases, including acute kidney injury (AKI). It is suggested that hypersuccinylation favors peroxisomal fatty acid oxidation (FAO) instead of mitochondrial. In addition, the medium-chain fatty acids (MCFAs) dodecanedioic acid (DC12) and octanedioic acid (DC8), upon FAO, generate succinyl-CoA, resulting in hypersuccinylation. DC8 is convenient, inexpensive, easily administered, and efficient. We believe this study could be translated in the future to clinical settings, which would highly benefit patients at high risk of AKI. Methods and ResultsTo test the protective roles of MCFAs during AKI, mice were fed with control, 10% DC12, or 10% DC8 diet, then, subjected to either ischemic-AKI, or cisplatin-AKI models. Supplementation was provided until sacrifice. Biochemical, histologic, genetic, and proteomic analysis were performed, the latter involving a lysine-succinylome-based analysis. Both DC8 and DC12 prevented the rise of AKI markers in mice that underwent renal injury. However, DC8 was even more protective against AKI than DC12. Finally, succinylome analysis evidenced that the kidneys of DC8-fed mice showed an extensive succinylation of peroxisomal activity-related proteins, and a decline in mitochondrial FAO, in comparison to control-fed mice. ConclusionDC8 supplementation drives renal protein hypersuccinylation, promoting a shift from mitochondrial to peroxisomal FAO, and protecting against AKI. Significance StatementLysine succinylation of proteins is shown to control several diseases, including acute kidney injury (AKI). Here we show that mice supplemented with the medium-chain fatty acid octanedioic acid successfully presented a high level of succinylation and were protected from both ischemia-reperfusion- and cisplatin-induced AKI. Moreover, our study demonstrates that peroxisomal activity was increased while mitochondrial activity was preserved, suggesting that the metabolism of diet-obtained medium-chain fatty acids by peroxisomes is renoprotective.

pathology↗