How does hyperglycaemia predispose to diabetic nephropathy?
Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
Wardle
E N
EN
D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006031:Glycosylation; D006493:Heparin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism
D013928:Thromboxane A2; D006493:Heparin; D011493:Protein Kinase C