Proximal Tubule Cell Hypothesis for Cardiorenal Syndrome in Diabetes

Department of Applied Molecular Medicine and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
International journal of nephrology 12/2010; 2011(2090-214X):957164. DOI: 10.4061/2011/957164
Source: PubMed


Incidence of cardiovascular disease (CVD) is remarkably high among patients with chronic kidney disease (CKD), even in the early microalbuminuric stages with normal glomerular filtration rates. Proximal tubule cells (PTCs) mediate metabolism and urinary excretion of vasculotoxic substances via apical and basolateral receptors and transporters. These cells also retrieve vasculoprotective substances from circulation or synthesize them for release into the circulation. PTCs are also involved in the uptake of sodium and phosphate, which are critical for hemodynamic regulation and maintaining the mineral balance, respectively. Dysregulation of PTC functions in CKD is likely to be associated with the development of CVD and is linked to the progression to end-stage renal disease. In particular, PTC dysfunction occurs early in diabetic nephropathy, a leading cause of CKD. It is therefore important to elucidate the mechanisms of PTC dysfunction to develop therapeutic strategies for treating cardiorenal syndrome in diabetes.

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Available from: Ryohei Kaseda, Dec 17, 2013
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    • "Phenotypic changes in proximal tubule cells (PTCs) are initial signs of DN (3,4), and consequent tubulointerstitial damage plays a central role in the progression to end-stage kidney disease (5). Furthermore, PTC dysfunction is likely to be involved in the development of CVD in diabetes (6). However, efficient biomarkers associated with the mechanism of PTC dysfunction in diabetes have not been established. "
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    ABSTRACT: Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.
    Biochemical and Biophysical Research Communications 02/2011; 407(1):108-12. DOI:10.1016/j.bbrc.2011.02.118 · 2.30 Impact Factor
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    Basic and Clinical Endocrinology Up-to-Date, 10/2011; , ISBN: 978-953-307-340-8
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