Effect of sodium (S)-2-hydroxyglutarate in male, and succinic acid in female Wistar rats against renal ischemia-reperfusion injury, suggesting a role of the HIF-1 pathway.

BACKGROUND: Ischemia-reperfusion (IR) injury is the main cause of delayed graft function in solid organ transplantation. Hypoxia-inducible factors (HIFs) control the expression of genes related to preconditioning against IR injury. During normoxia, HIF-α subunits are marked for degradation by the egg-laying defective nine homolog (EGLN) family of prolyl-4-hydroxylases. The inhibition of EGLN stabilizes HIFs and protects against IR injury. The aim of this study was to determine whether the EGLN inhibitors sodium (S)-2-hydroxyglutarate [(S)-2HG] and succinic acid (SA) have a nephroprotective effect against renal IR injury in Wistar rats. METHODS: (S)-2HG was synthesized in a 22.96% yield from commercially available L-glutamic acid in a two-step methodology (diazotization/alkaline hydrolysis), and its structure was confirmed by nuclear magnetic resonance and polarimetry. SA was acquired commercially. (S)-2HG and SA were independently evaluated in male and female Wistar rats respectively after renal IR injury. Rats were divided into the following groups: sham (SH), nontoxicity [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg], IR, and compound+IR [(S)-2HG: 12.5 or 25 mg/kg; SA: 12.5, 25, or 50 mg/kg]; independent SH and IR groups were used for each assessed compound. Markers of kidney injury (BUN, creatinine, glucose, and uric acid) and liver function (ALT, AST, ALP, LDH, serum proteins, and albumin), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), oxidative stress biomarkers (malondialdehyde and superoxide dismutase), and histological parameters (tubular necrosis, acidophilic casts, and vascular congestion) were assessed. Tissue HIF-1α was measured by ELISA and Western blot, and the expression of Hmox1 was assessed by RT-qPCR. RESULTS: (S)-2HG had a dose-dependent nephroprotective effect, as evidenced by a significant reduction in the changes in the BUN, creatinine, ALP, AST, and LDH levels compared with the IR group. Tissue HIF-1α was only increased in the IR group compared to SH; however, (S)-2HG caused a significant increase in the expression of Hmox1, suggesting an early accumulation of HIF-1α in the (S)-2HG-treated groups. There were no significant effects on the other biomarkers. SA did not show a nephroprotective effect; the only changes were a decrease in creatinine level at 12.5 mg/kg and increased IR injury at 50 mg/kg. There were no effects on the other biochemical, proinflammatory, or oxidative stress biomarkers. CONCLUSION: None of the compounds were hepatotoxic at the tested doses. (S)-2HG showed a dose-dependent nephroprotective effect at the evaluated doses, which involved an increase in the expression of Hmox1, suggesting stabilization of HIF-1α. SA did not show a nephroprotective effect but tended to increase IR injury when given at high doses.

Evidence of transmission and risk factors for influenza A virus in household dogs and their owners.

BACKGROUND: The possible transmission of influenza A virus between dogs and humans is important, as in Mexico City there are approximately 1·2 million dogs. We present the first evidence of influenza A virus infection in household dogs in Mexico. OBJECTIVES: The objective of this study was to identify the presence of antibodies against influenza A virus in dogs and their owners, as well as the presence of RNA of influenza A virus in nasal exudates of dogs and, thereby, assess the possible transmission of the virus between humans and dogs. METHODS: Serum samples from household dogs and their owners were analyzed to detect the presence of antibodies against three subtypes of human influenza virus (H1N1pdm09, H1N1, and H3N2), as well as subtype H3N8 of equine influenza. We analyzed dog nasal exudates to detect influenza viral RNA. The relationship between the seropositivity of dogs and various factors (age, sex, constantly at home, and seropositivity of owners) was statistically analyzed. RESULTS: Seroprevalence for human influenza in dogs was 0·9% (1 of 113), and it was 4% (5 of 113) for equine influenza. In humans, seroprevalence was 22% for subtype H1N1pdm09, 20% for subtype H1N1, and 11% for subtype H3N2. No significant association (P>0·05) was found between seropositivity and any of the assessed factors. Furthermore, no viral RNA was detected in the nasal exudate samples. CONCLUSIONS: Results revealed seroprevalence of the influenza virus in household dogs in Mexico City. It can be assumed that dogs are currently becoming infected with different subtypes of influenza viruses.