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

Abstract

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 α3α4α5 network with the α1α1α2 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 TGFβ 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.

Figure 1. Factors in the pathogenesis of glomerular disease in Alport syndrome

A, increased biomechanical strain from hypertension, abnormal GBM, altered podocyte cytoskeleton and cell adhesion. B, lamellated or thinned GBM with different collagen IV and laminin molecules, and increased MMP proteolysis. C, podocyte α2β1 integrin and DDR1 detect abnormal collagen IV. D, altered podocyte adhesion and actin/cytoskeleton. E, nuclear peroxisome proliferator-activated receptor γ (PPARγ) downregulation of SD slit diaphragm gene transcription and podocyte apoptosis (based on Noone & Licht, 2013).

Figure 2. Pathogenesis of tubulointerstitial disease and disease progression in Alport syndrome

The figure is based on Noone & Licht, .