Mechanisms of Renal Graft Chronic Injury and Progression to Interstitial Fibrosis

Abstract

Following transplantation, the kidney is exposed to many different injuries which result in inflammation, overproduction of extracellular matrix, interstitial fibrosis and progressive loss of renal function. To date, treatment options for patients with progressive graft dysfunction are very limited. The development of new therapies requires a better understanding of the pathogenesis of transplant interstitial fibrosis and specific biomarkers to identify patients with progressive transplant fibrosis and monitor response to new therapies. Here, we review our current understanding of how and why extracellular matrix accumulates and the relationship between fibrosis and inflammation. In particular, we focus on the role of heparan sulphate that regulates recruitment, migration and differentiation of interstitial cells and also acts as a reservoir for multiple cytokines and growth factors.

Heparan sulfate in chronic kidney diseases: Exploring the role of 3-O-sulfation

“…HS is an abundant component of extracellular matrices and cell surfaces, where it is found covalently bound to the core protein of HS proteoglycans (HSPG) [4]. HSPGs regulate the function of growth factors and chemokines by preventing their proteolysis, regulating receptor activation and anchoring them to the extracellular matrix and to the cell surface [5][6][7]. Due to its role in leukocyte recruitment and in the binding and modulation of pro-fibrotic factors such as TGF [8], HS plays a crucial role in the development of fibrosis [9,10].…”

Regulation of Chemokine Function: The Roles of GAG-Binding and Post-Translational Nitration

“…These give rise to N -, 6- O , or (albeit rarely) 3- O -sulphation of the glucosamine (GlcNS), as well as epimerisation and subsequent 2- O -sulphation of the glucuronic acid. The family of enzymes responsible for these modifications includes N -deacetylase/ N -sulphotranferases (NDSTs 1/2/3/4), 2- O -sulphotransferases (HS2ST), 6- O -sulphotransferases (HS6ST), and 3- O -sulphotransferases (HS3ST) [ 44 , 45 ]. Mature HS can also be modified on the cell surface glycocalyx by specific sulphatases (SULF1 and SULF2).…”