Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment

作者：Savige Judy^*

来源：The Journal of Physiology, 2014, 592(18): 4013-4023.

DOI：10.1113/jphysiol.2014.274449

The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have come to realise that permselectivity depends on size and not necessarily charge, that the molecular sieve depends on the podocyte contractile apparatus and is highly dynamic, and that protein uptake by proximal tubular epithelial cells stimulates signalling and the production of transcription factors and inflammatory mediators. Alport syndrome is the second commonest monogenic cause of renal failure after autosomal dominant polycystic kidney disease. Eighty per cent of patients have X-linked disease caused by mutations in the COL4A5 gene. Most of these result in the replacement of the collagen IV 345 network with the 112 heterotrimer. Affected membranes also have ectopic laminin and increased matrix metalloproteinase levels, which makes them more susceptible to proteolysis. Mechanical stress, due to the less elastic membrane and hypertension, interferes with integrin-mediated podocyte-GBM adhesion. Proteinuria occurs when urinary levels exceed tubular reabsorption rates, and initiates tubulointerstitial fibrosis. The glomerular mesangial cells produce increased TGF and CTGF which also contribute to glomerulosclerosis. Currently there is no specific therapy for Alport syndrome. However treatment with angiotensin converting enzyme (ACE) inhibitors delays renal failure progression by reducing intraglomerular hypertension, proteinuria, and fibrosis. Our greater understanding of the mechanisms underlying the GBM changes and their consequences in Alport syndrome have provided us with further novel therapeutic targets.

• 出版日期2014-9-15