Oral high dose vitamin B12 decreases renal superoxide and post-ischemia/reperfusion injury in mice
Feng Li,
Edward M. Bahnson,
Jennifer Wilder,
Robin Siletzky,
John Hagaman,
Volker Nickekeit,
Sylvia Hiller,
Azraa Ayesha,
Lanfei Feng,
Jerrold S. Levine,
Nobuyuki Takahashi,
Nobuyo Maeda-Smithies
Affiliations
Feng Li
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA; Corresponding author.
Edward M. Bahnson
Department of Surgery, The University of North Carolina, Chapel Hill, NC, 27599, USA
Jennifer Wilder
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Robin Siletzky
Department of Surgery, The University of North Carolina, Chapel Hill, NC, 27599, USA
John Hagaman
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Volker Nickekeit
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA; Division of Nephropathy, School of Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Sylvia Hiller
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Azraa Ayesha
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Lanfei Feng
Section of Nephrology, Department of Medicine, University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA
Jerrold S. Levine
Section of Nephrology, Department of Medicine, University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA
Nobuyuki Takahashi
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA; Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School, Sendai, Japan
Nobuyo Maeda-Smithies
Dept of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC, 27599, USA
Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), a potentially fatal syndrome characterized by a rapid decline in kidney function. Excess production of superoxide contributes to the injury. We hypothesized that oral administration of a high dose of vitamin B12 (B12 - cyanocobalamin), which possesses a superoxide scavenging function, would protect kidneys against IRI and provide a safe means of treatment. Following unilateral renal IR surgery, C57BL/6J wild type (WT) mice were administered B12 via drinking water at a dose of 50 mg/L. After 5 days of the treatment, plasma B12 levels increased by 1.2-1.5x, and kidney B12 levels increased by 7-8x. IRI mice treated with B12 showed near normal renal function and morphology. Further, IRI-induced changes in RNA and protein markers of inflammation, fibrosis, apoptosis, and DNA damage response (DDR) were significantly attenuated by at least 50% compared to those in untreated mice. Moreover, the presence of B12 at 0.3 μM in the culture medium of mouse proximal tubular cells subjected to 3 hr of hypoxia followed by 1 hr of reperfusion in vitro showed similar protective effects, including increased cell viability and decreased reactive oxygen species (ROS) level. We conclude that a high dose of B12 protects against perfusion injury both in vivo and in vitro without observable adverse effects in mice and suggest that B12 merits evaluation as a treatment for I/R-mediated AKI in humans.
