5 Increased dynamin expression precedes proteinuria in glomerular disease 97 Although the used Hudy 1 antibody does not discern between DNM1 and DNM2 protein, the higher Dnm2 mRNA levels suggest that Dnm2 is the more prevalent type of dynamin, as also reported by others.(14) We found that the glomerular levels of dynamin protein were increased primarily in patients with minimal change disease (MCD) and lupus nephritis. Schiffer et al. recently proposed that dynamin’s principal role in maintaining podocyte structure and preventing proteinuria is independent of the underlying disease pathogenesis.(75) Our results are consistent with this notion, given that lupus nephritis is considered to be immunological in origin, whereas MCD is not.(85, 86) Sever et al. previously reported the levels of CTSL mRNA were increased in the glomeruli of patients with acquired proteinuric disease. (13) Notably, the levels of CTSL mRNA expression were increased in patients with focal segmental glomerulosclerosis (FSGS) and in patients with diabetic nephropathy, but not in patients with MCD. Interestingly, we found that dynamin expression was significantly increased in patients with MCD, but not in patients with FSGS or diabetic nephropathy; Sever et al. did not measure CTSL mRNA in patients with lupus nephritis. In our study, we found significantly more cathepsin L protein in glomeruli of patients with minimal change disease, lupus nephritis, and IgA nephropathy. Although we did see an increase in glomerular cathepsin L positive area percentage in DN patients, as also reported by Sever et al., this increase was not statistically significant. Thus, taken together, these results suggest that in human proteinuric disease, the interplay between cathepsin L and dynamin is part of a regulatory system influenced by proteinuria, as proposed previously.(13) Dynamin’s protective effect on the GFB could be effected through its role in nephrin turnover, as suggested by other groups.(14, 87-89) Nephrin (encoded in rats by the Nphs1 gene) is a core component of the glomerular slit diaphragm.(16) In podocytes, nephrin is internalized by clathrin-mediated endocytosis and clathrin-independent raft-mediated endocytosis, both of which are dynamin-dependent processes.(88) We previously reported that Nphs1 mRNA levels are increased significantly in Dahl rats by 10 weeks of age, although the pattern of nephrin protein is focal and segmental rather than linear, and effacement of the podocyte foot process occurs.(17) In this study, we found that the levels of Dnm1 and Dnm2 mRNA are significantly lower at 10 weeks of age compared to younger ages. These results suggest that the relative decrease in Dnm1 and Dnm2 mRNA in Dahl rats at later ages results in a loss of sufficient nephrin turnover, which then leads to reduced protection against podocyte pathology.
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