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.
Highlights
Chronic kidney disease (CKD) is a major health issue worldwide [1]
Dahl rats under a low dietary salt intake developed significant proteinuria beginning at 6 weeks of age; in contrast, spontaneously hypertensive rats (SHR) rats did not develop proteinuria, even at 10 weeks of age (Figure 1A)
We found a significant increase in the glomerular levels of Dnm2 and Dnm1 mRNA in Dahl rats prior to the onset of albuminuria
Summary
Chronic kidney disease (CKD) is a major health issue worldwide [1]. The progression of CKD is accompanied by a reduction in the glomerular filtration rate and subsequent proteinuria. In order to develop new therapeutic strategies for CKD, it is important to understand the mechanisms and processes that underlie glomerular filtration. The glomerular filtration barrier (GFB) consists of several components, including the interdigitating foot processes of podocytes, the glomerular basement membrane, and a glycocalyx-covered fenestrated endothelium. Disrupting the GFB allows the passage of proteins into the urinary space. Under normal conditions, these proteins are reabsorbed by proximal tubular epithelial cells; if the reabsorption mechanism is impaired or saturated, proteinuria can develop
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