Discussion
albuminuria, GEnGlx damage, diabetes, STZ-induced diabetic, diabetic, MR, glomerular dysfunction
DISEASE, DYSFUNCTION, ADVERSE EFFECTS, PEARLY DISEASE, DIABETES
Using a rat model of diabetes, we have demonstrated that upregulation of MMPs, GEnGlx damage, and glomerular dysfunction develop rapidly before other visible markers of DN. MR antagonism preserved the GEnGlx and restored GFB function. In vitro, using human GEnC exposed to a diabetic environment, we also observed upregulation of MMPs and glycocalyx damage, effects ameliorated by MR antagonism. In addition, we confirmed that GEnGlx damage occurs in human DN and may contribute to the disease phenotype. Finally, we have demonstrated that MR antagonism in human DN reduced MMP activity, with associated reductions in albuminuria. Together, these data suggest that alternative approaches to limit MMP activity and GEnGlx damage may reproduce the effect of MR inhibition while limiting side effects.STZ-induced diabetic rats provide a good model of early changes in DN (The GEnGlx plays an important role in GFB function, limiting albumin permeability (Hyaluronan is a key Glx component that is shed in diabetes (MR-induced MMPs are likely to contribute to Glx damage in DN. In mice, we have demonstrated increased MMP activity induced by excess aldosterone (MR is widely expressed by vascular endothelial cells, including GEnC, (In humans, the absence of GBM and podocyte changes in early disease, along with systemic endothelial and Glx dysfunction seen in both type 1 (In summary, we have shown that MR antagonism prevented damage to the GEnGlx and normalized glomerular albumin permeability in early DN. By applying potentially novel, validated techniques, we have demonstrated that GEnGlx damage may contribute to the disease phenotype in human DN. In addition, MR antagonism in DN reduced MMP activity, highlighting a mechanism of Glx protection. Alternative approaches to block MR-induced GEnGlx dysfunction, to reproduce the benefit of MR antagonists in DN without the adverse effects, warrant further investigation.