Increased dynamin expression precedes proteinuria in glomerular disease

Abstract

Dynamin plays an essential role in maintaining the structure and function of the glomerular filtration barrier. Specifically, dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, and knocking down dynamin expression causes proteinuria. Moreover, promoting dynamin oligomerization with Bis‐T‐23 restores podocyte function and reduces proteinuria in several animal models of chronic kidney disease. Thus, dynamin is a promising therapeutic target for treating chronic kidney disease. Here, we investigated the pathophysiological role of dynamin under proteinuric circumstances in a rat model and in humans. We found that glomerular Dnm2 and Dnm1 mRNA levels are increased prior to the onset of proteinuria in a rat model of spontaneous proteinuria. Also, in zebrafish embryos, we confirm that knocking down dynamin translation results in proteinuria. Finally, we show that the glomerular expression of dynamin and cathepsin L protein is increased in several human proteinuric kidney diseases. We propose that the increased expression of glomerular dynamin reflects an exhausted attempt to maintain and/or restore integrity of the glomerular filtration barrier. These results confirm that dynamin plays an important role in maintaining the glomerular filtration barrier, and they support the notion that dynamin is a promising therapeutic target in proteinuric kidney disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

More expression, less function: cleaved dynamin in glomerular kidney disease

“…Deciphering the mechanisms leading to development of proteinuria is one of the major goals of nephrologists. A recent study published in The Journal of Pathology provides further evidence showing how dynamin is modulated during human proteinuric disease [1]. This study dovetails mechanistic reports on the critical role of dynamin in glomerular disease and should aid a better molecular description of the underlying process as therapies to target dynamin are being developed.…”

“…This study goes even further in identifying the degree of dynamin expression with regard to proteinuria by immunohistochemical analysis of kidney biopsies from patients with various proteinuric kidney diseases (minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis and diabetic nephropathy) and detected positive staining primarily in podocytes, tubular epithelial cells and endothelial cells of larger vessels . Given the use of a dynamin antibody that recognizes the C‐terminal tail of the enzyme, the increased expression is likely an attempt to counterbalance the increase in expression and activity of cathepsin L in injured podocytes.…”

“…Both mechanisms work synergistically to some degree to maintain dynamin's role in supporting the structure and function of glomerular filtration. The elevated dynamin expression in the glomeruli of rats even before the onset of proteinuria may represent a compensatory mechanism for impaired glomerular filtration, which later becomes futile and fails to prevent proteinuria as disease progresses . These findings represent a major advance in defining a plausible link between dynamin and actin cytoskeleton of podocytes and reveal the physiological significance of dynamin as a potential therapeutic target to restore glomerular filtration and to treat proteinuria across a wide spectrum of CKDs.…”

Overexpression of Myo1e promotes albumin endocytosis by mouse glomerular podocytes mediated by Dynamin

“…Dynamin plays a crucial role in maintaining the structure and function of the glomerular filtration barrier. Dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, furthermore, knockdown of dynamin leads to proteinuria (Khalil et al, 2019). Dynamindependent podocyte endocytosis is one of the pathways of albumin endocytosis.…”

Peer Review #2 of "Overexpression of Myo1e promotes albumin endocytosis by mouse glomerular podocytes mediated by Dynamin (v0.2)"

“…Dynamin plays a crucial role in maintaining the structure and function of the glomerular filtration barrier. Dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, furthermore, knockdown of dynamin leads to proteinuria (Khalil et al 2019). Dynamin-dependent podocyte endocytosis is one of the pathways of albumin endocytosis.…”