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Abstract

The number of individuals diagnosed with diabetes continues to increase year over year, with roughly half a billion people affected worldwide. Diabetes-related comorbidities are an extra burden on patients and account for many deaths through cardiovascular events (heart attack and stroke) or microvascular organ damage (nephropathy, neuropathy, and retinopathy). In Germany, diabetic nephropathy is the leading cause for kidney failure which leaves patients no other choice than renal dialysis or waiting for an organ transplant. This puts a tremendous financial strain on the public health sector. Therefore, therapies are needed to prevent or slow down the progression of diabetes-related alterations of the vasculature or organs. Proteotoxic properties of glycated proteins (so called advanced glycation end products or AGEs), have been marked as one pathway leading to diabetic nephropathy, especially adducts from the reactive dicarbonyl methylglyoxal (MG). In this regard, the heat-shock proteins Hspa1a and Hspa1b were chosen as a target, as they have the greatest importance in addressing protein misfolding and aggregation. In this work, the loss of Hspa1a/Hspa1b on methylglyoxal-induced endothelial dysfunction was studied in vitro, whilst the effect on diabetic nephropathy was studied in vivo using an experimental model of type 1 diabetes. A loss of Hspa1a/Hspa1b did lead to an increase of MG-derived advanced glycation end products in vitro. However, clearance of MG-modified proteins was unaffected. In addition, oxidative stress and expression of inflammation markers were increased. Furthermore, MG triggered changes of the mitochondrial network after acute and chronic stress in Hspa1a/Hspa1b knockout cells, whereas mitochondrial respiration remained unchanged. In vivo, the kidneys from Hspa1a/Hspa1b knockout mice showed no differences in renal parameters, either in control or STZ-diabetic mice. Mesangial matrix was found to be increased in the STZ-diabetic mice, which was enhanced in the Hspa1a/Hspa1b knockout mice. Interestingly, the lack of Hspa1a/Hspa1b seemed to attenuate albuminuria. In conclusion, the in vitro results indicate that a deficiency of Hspa1a/Hspa1b shortly increases a MG-H1 accumulation under acute MG-stress and induces changes in the mitochondrial network. The in vivo data suggest that a loss of Hspa1a/Hspa1b might be protective in respect of albuminuria and might be an interesting therapeutic target.