The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats
| Autor: | Maurits Roorda, Edwin L de Vrij, P. Vogelaar, Guido Krenning, Hjalmar R. Bouma, M. C. Houwertjes, Adrianus Cornelis Van Der Graaf, Robert H. Henning, Maaike Goris |
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| Přispěvatelé: | Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male renal injury Organ Preservation Solutions 030232 urology & nephrology Renal function ACUTE KIDNEY INJURY ISCHEMIA-REPERFUSION INJURY Hypothermia Mitochondrion Pharmacology 6-hydroxychromanol medicine.disease_cause MEMBRANES MECHANISMS Diabetic nephropathy MITOCHONDRIAL-FUNCTION 03 medical and health sciences 0302 clinical medicine Cryoprotective Agents ANTIOXIDANTS medicine Animals Humans Chromans Rats Wistar Rewarming Transplantation Kidney Protein nitrosylation business.industry hypothermia/rewarming ALPHA-TOCOPHEROL Acute kidney injury TUBULAR CELLS medicine.disease PREVENTION DYSFUNCTION Rats mitochondria Oxidative Stress 030104 developmental biology medicine.anatomical_structure Nephrology Reperfusion Injury medicine.symptom business Oxidative stress |
| Zdroj: | Nephrology, Dialysis, Transplantation, 33(12), 2128-2138. Oxford University Press |
| ISSN: | 1460-2385 0931-0509 |
| Popis: | Background. Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats.Methods. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 mu g/kg/h) undergoing H/R at 15 degrees C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed.Results. H/R injury in vitro lowered cell viability by 94 +/- 61%, which was counteracted dose-dependently by multiple 6-hydroxy-chomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 50-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation.Conclusions. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols limit DNA damage, but only SUL-109 also prevented protein nitrosylation in tubular cells. Therefore SUL-109 offers a promising therapeutic strategy to preserve kidney mitochondrial function. |
| Databáze: | OpenAIRE |
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