Molecular and Cellular Mechanisms Underlying the Initiation and Progression of Alport Glomerular Pathology

Abstract

Alport syndrome results from a myriad of variants in the COL4A3, COL4A4, or COL4A5 genes that encode type IV (basement membrane) collagens. Unlike type IV collagen α1(IV)2α2(IV)1 heterotrimers, which are ubiquitous in basement membranes, α3/α4/α5 have a limited tissue distribution. The absence of these basement membrane networks causes pathologies in some, but not all these tissues. Primarily the kidney glomerulus, the stria vascularis of the inner ear, the lens, and the retina as well as a rare link with aortic aneurisms. Defects in the glomerular basement membranes results in delayed onset and progressive focal segmental glomerulosclerosis ultimately requiring the patient to undergo dialysis and if accessible, kidney transplant. The lifespan of patients with Alport syndrome is ultimately significantly shortened. This review addresses the consequences of the altered glomerular basement membrane composition in Alport syndrome with specific emphasis on the mechanisms underlying initiation and progression of glomerular pathology.

Potential Renal Damage Biomarkers in Alport Syndrome—A Review of the Literature

“…In AS, changes in GBM composition are the starting point of the pathogenic pathway that involves all three cell types of the glomerulus. The thinner GBM has fewer interchain disulfide crosslinks, which diminishes the elasticity of glomerular tufts; this makes them susceptible to mechanical forces of normal glomerular capillary flow, which has the highest capillary pressure in the human body [8][9][10]. One of the earliest events in AS is the significantly elevated expression of endothelin-1 (ET-1) in the endothelial cells, which seems to be related to an elevated biomechanical strain on glomerular capillary tufts.…”

“…ET-1 elevation causes the activation of endothelin A receptors (ETARs), which in turn leads to downstream activation of CDC42, which results in mesangial filopodia. The mesangial filopodia progressively invade the subendothelial space of GBM, with deposition of mesangial matrix proteins, including laminin 211 [10,11]. Laminin 211 activates focal adhesion kinase (FAK) on podocytes, which activates NF-kB (Nuclear factor kappa B), resulting in elevated expression of pro-inflammatory cytokines as well as matrix metalloproteinases.…”

“…Laminin 211 activates focal adhesion kinase (FAK) on podocytes, which activates NF-kB (Nuclear factor kappa B), resulting in elevated expression of pro-inflammatory cytokines as well as matrix metalloproteinases. In addition, laminin 211 contributes to altering GBM permeability and appears to be important to the progressive increase in proteinuria [10]. The deposition of mesangial matrix proteins in the GBM induces podocyte injury [10].…”

“…In addition, laminin 211 contributes to altering GBM permeability and appears to be important to the progressive increase in proteinuria [10]. The deposition of mesangial matrix proteins in the GBM induces podocyte injury [10]. Progressive loss of podocytes causes glomerulosclerosis, which is associated with reduced glomerular blood perfusion to post-glomerular peritubular capillaries and reduced or absent glomerular filtrate, which together induce ischemic and inflammatory tubular cell injury, death, and peritubular inflammation and scarring [12].…”

Characterization of peroxidasin expression in histologically normal human adult and fetal kidney tissue

“…Therefore, defects in the architecture of kidney BMs are deleterious to cell-to-BM binding, which may result in loss of cell orientation and anomalous cell function, leading to tissue disruption; loss of GBM and TBM barrier functions; and to impaired tissue development and repair [1]. Indeed, genetic defects in the COL4 network, which forms the major structural scaffold of BMs, have a substantial impact on the mechanical stability of BMs, as observed in the GBM of patients with Alport syndrome [11]. The lower stiffness of kidney TBM observed in PXDN knockout mice, with deficient sulfilimination activity, provides direct experimental evidence that COL4 sulfilimine crosslinking contributes to the mechanical properties of kidney BMs, conferring structural reinforcement to the COL4 networks [6].…”