2018FatahHRPhD.pdf (4.43 MB)
Reduced Proximal Tubular Expression of Megalin and Neonatal Fc Receptor in Proteinuria: The Role of Matrix Metalloproteinases
thesisposted on 2018-01-31, 15:24 authored by Hiwa Ramadhan Fatah
Proteinuria is clearly associated with the progression of chronic kidney disease (CKD) but the mechanisms underlying this relationship remain unclear. Recent evidence suggests that altered proximal tubular (PT) handling of filtered proteins may significantly modulate urine protein excretion and progressive renal disease. Megalin and neonatal Fc receptor (FcRn) are endocytic receptors responsible for the PT reabsorption of glomerular ultrafiltered proteins by receptor-mediated endocytosis (RME) and transcytosis, and are expressed on the luminal surface of the PT. This study aimed to investigate the expression and turnover of megalin and FcRn in proteinuria, and the possible mechanisms underlying down-regulation of expression of these receptors. In protein overload proteinuria (POP), the PT expression of megalin and FcRn were both downregulated compared to control animals. In addition, significant amount of both receptor were detected in the urine of proteinuric animals. This reduction in megalin and FcRn protein expression was accompanied by a significant increase in the urinary excretion of plasma proteins including the most abundant albumin. Increased expression and activity of both matrix metalloproteinase (MMP) and gamma secretase (γ-secretase) was evident in proteinuric animals and was paralleled with the urinary excretion of both megalin and FcRn. Megalin was previously identified to undergo regulated intramembrane proteolysis (RIP). RIP includes the MMP-mediated cleavage of the extracellular domain of megalin which in turn excreted into the urine, and the subsequent cleavage of the intracellular domain by γ-secretase. A synthetic inhibitor of MMPs, batimastat (BB-94) significantly reduced urinary excretion and also preserved the PT expression of megalin. In addition, inhibition of MMPs appeared to be antiproteinuric by markedly reducing urinary excretion of albumin and plasma proteins. The urinary excretion of FcRn was also reduced in BB-94 treated animals but the mechanism of this reduction was not clear. Further, BB-94 treatment preserved PT expression of FcRn in proteinuric animals. The POP model was developed to investigate the degree of tubulointerstitial damage in experimental animals. Injury was detected in the interstitium of proteinuric animals with significant increases in inflammatory markers including tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and the transforming growth factor-beta (TGF-β) as well as interstitial collagen deposition and marked interstitial infiltration of macrophages (F4/80). Blockade of MMP in proteinuric animals significantly reduced the expression of these markers in the kidney and abrogated the progression of interstitial inflammation and fibrosis. In summary this is the first study to correlate the reduced expression of megalin and FcRn, and the urinary excretion of these receptors with the increased cellular activity of MMP and the possible occurrence of RIP in vivo. Inhibition of MMP could be of great importance in treating proteinuria and the progression of tubulointerstitial inflammation and fibrosis, the most characteristic features of CKD.
Date of award2018-01-30
Author affiliationDepartment of Infection, Immunity and Inflammation
Awarding institutionUniversity of Leicester