The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity.

The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity.
Am J Pathol. 2018 Nov 07;:
Authors: Kameyama H, Uchimura K, Yamashita T, Kuwabara K, Mizuguchi M, Hung SC, Okuhira K, Masuda T, Kosugi T, Ohgita T, Saito H, Ando Y, Nishitsuji K
Abstract
The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of TTR in an HS S-domain-dependent manner. Interactions of cells with TTR fibrils and cytotoxicity of these fibrils also depended on HS S-domains at the cell surface. Furthermore, glypican-5 (GPC5), encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the ATTR amyloidosis kidney. Our study thus provides a novel insight into the pathological roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer ...

Source: The American Journal of Pathology - November 7, 2018 Category: Pathology Authors: Kameyama H, Uchimura K, Yamashita T, Kuwabara K, Mizuguchi M, Hung SC, Okuhira K, Masuda T, Kosugi T, Ohgita T, Saito H, Ando Y, Nishitsuji K Tags: Am J Pathol Source Type: research