5 Increased dynamin expression precedes proteinuria in glomerular disease 85 Introduction Chronic kidney disease (CKD) is a major health issue worldwide.(2) The progression of CKD is accompanied by a reduction in 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 then reabsorbed by proximal tubular epithelial cells; however, if the reabsorption mechanism is impaired or saturated, proteinuria can develop. Dynamin is a recently identified protein that plays an important role in maintaining GFB integrity. This 96 kDa GTPase is expressed both in glomerular podocytes and in tubular epithelial cells.(13, 73) Within the GFB, dynamin has three identified functions: i) dynamin is involved in the turnover of nephrin (14); ii) dynamin interacts directly with actin and actin-regulatory proteins (12); and iii) dynamin is involved in the endocytosis of albumin by podocytes (74). Several groups have reported that loss of dynamin using a genetic knockdown model or via cleavage with the endopeptidase cathepsin L results in proteinuria.(13, 14, 75) Moreover, Schiffer et al. demonstrated that dynamin is a potential therapeutic target in CKD.(75) Specifically, the authors reported beneficial effects of treating several animal models of proteinuria with Bis-T-23, a small molecule compound that stimulates the oligomerization of dynamin to form a 72-subunit helical structure.(11) Importantly, Schiffer et al. found that administering Bis-T-23 restored the ultrastructure of podocyte foot processes, decreased proteinuria, lowered mesangial collagen IV deposition, reduced mesangial matrix expansion, and prolonged survival.(75) Ono et al. also showed that Bis-T-23 treatment prevented albuminuria and attenuated alterations in foot process formation in an experimental mouse model .(76) Although these studies indicate that dynamin plays an important role in maintaining GFB structure and function, the majority of this research relied on the observation of morphological and/or functional changes in the kidney after genetic manipulation or other alterations in dynamin. Thus, intrinsic changes in dynamin expression under proteinuric conditions have not been investigated in animal models or patients. Here, we report that dynamin expression is increased in proteinuric conditions. We show that glomerular Dnm2 and Dnm1 mRNA levels are increased in a rat model of spontaneous proteinuria prior to the onset of proteinuria. Also, we show that knocking
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