Abstract
BackgroundSuppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT.MethodsLivers were explanted from Lewis rats and implanted after 18 h cold storage. Kidney and blood were collected 18 h after LT.ResultsIn the kidney, oxidative phosphorylation (OXPHOS) proteins ATP synthase-β and NADH dehydrogenase-3 decreased 44% and 81%, respectively, with marked reduction in associated mRNAs. Renal PGC-1α, the major regulator of MB, decreased 57% with lower mRNA and increased acetylation, indicating inhibited synthesis and suppressed activation. Mitochondrial transcription factor-A, which controls mtDNA replication and transcription, protein and mRNA decreased 66% and 68%, respectively, which was associated with 64% decreases in mtDNA. Mitochondrial fission proteins Drp-1 and Fis-1 and mitochondrial fusion protein mitofusin-1 all decreased markedly. In contrast, PTEN-induced putative kinase 1 and microtubule-associated protein 1A/1B-light chain 3 increased markedly after LT, indicating enhanced mitophagy. Concurrently, 18- and 13-fold increases in neutrophil gelatinase-associated lipocalin and cleaved caspase-3 occurred in renal tissue. Both serum creatinine and blood urea nitrogen increased >2 fold. Mild to moderate histological changes were observed in the kidney, including loss of brush border, vacuolization of tubular cells in the cortex, cast formation and necrosis in some proximal tubular cells. Finally, myeloperoxidase and ED-1 also increased, indicating inflammation.ConclusionSuppression of MB, inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT.
Highlights
Orthotopic liver transplantation (LT) is the only proven therapy for end-stage liver diseases [1,2,3,4,5]
This study investigated whether disrupted mitochondrial homeostasis plays a role in acute kidney injury (AKI) after LT
Suppression of mitochondrial biogenesis (MB), inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT
Summary
Orthotopic liver transplantation (LT) is the only proven therapy for end-stage liver diseases [1,2,3,4,5]. The incidence of perioperative acute kidney injury (AKI) in liver transplant recipients varies significantly, ranging from 17% to 95% [7,9,10,11,12,13]. After LT, 5–30% of recipients have to receive renal replacement therapy due to severe AKI [7,11]. AKI increases infection, sepsis, and acute rejection and substantially decreases patient survival after LT [11,14,15,16]. Acute renal dysfunction in LT recipients prolongs stays in intensive care units and the hospital, and increases re-hospitalization, the need for postoperative dialysis, and the cost of care. Suppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT
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