Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy

The Latest Iteration of IPCC Uncertainty Guidance: An Author Perspective

The latest iteration of Intergovernmental Panel on Climate Change (IPCC) uncertainty guidance is simpler and easier to use than the previous version. However, its primary focus remains assessing “what is at risk” under climate change, thus is most suitable for dealing with the scientific uncertainties in Working Group I and part of Working Group II findings. I distinguish between tame and complex risks, arguing that the guidance is most suited to assessing tame risks. Climate change is a complex risk, and as such as can be divided into idealized, calculated and perceived risks. While science has claims to objectivity, risk has a specific value component: when measuring gain and loss, calculated risks compete with risky options to manage those risks. The IPCC is charged with calculating risk (IPCC 2007, p22) but the communication of key findings takes place in an environment of competing perceived risks. Recommendations for managing this complex environment include separating scientific and risk-based findings, treating uncertainties for each separately; strengthening the philosophical basis of uncertainty management; application of a methodical scientific research program; clearly communicating competing findings, especially in the social sciences; and application of multiple frame to policy-relevant findings as reflected in the literature