Translational research : the journal of laboratory and clinical medicine
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The development of new and specific treatment options for kidney disease in general and glomerular diseases in specific has lagged behind other fields like heart disease and cancer. As a result, nephrologists have had to test and adapt therapeutics developed for other indications to treat glomerular diseases. One of the major factors contributing to this inertia has been the poor understanding of disease mechanisms. ⋯ Because many of these patients develop nephrotic syndrome, understanding the relationship of proteinuria, the primary driver in this syndrome, with hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, edema, and lipiduria could provide valuable insight. The recent unraveling of the relationship between proteinuria and hypertriglyceridemia mediated by free fatty acids, albumin, and the secreted glycoprotein angiopoietin-like 4 (Angptl4) offers a unique opportunity to develop novel therapeutics for glomerular diseases. In this review, the therapeutic potential of mutant forms of Angptl4 in reducing proteinuria and, as a consequence, alleviating the other manifestations of nephrotic syndrome is discussed.
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Renal fibrosis is the hallmark of virtually all progressive kidney diseases and strongly correlates with the deterioration of kidney function. The renin-angiotensin-aldosterone system blockade is central to the current treatment of patients with chronic kidney disease (CKD) for the renoprotective effects aimed to prevent or slow progression to end-stage renal disease (ESRD). However, the incidence of CKD is still increasing, and there is a critical need for new therapeutics. ⋯ These include strategies targeting chemokine pathways via CC chemokine receptors 1 and 2 to modulate the inflammatory response, inhibition of phosphodiesterase to restore nitric oxide-cyclic 3',5'-guanosine monophosphate function, inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4 to suppress reactive oxygen species production, and inhibition of endothelin 1 or tumor necrosis factor α to ameliorate progressive renal fibrosis. Furthermore, a brief overview of some of the biomarkers of kidney fibrosis is currently being explored that may improve the ability to monitor antifibrotic therapies. It is hoped that evidence based on the preclinical and clinical data discussed in this review leads to novel antifibrotic therapies effective in patients with CKD to prevent or delay progression to ESRD.
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Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. ⋯ Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein-coupled receptor kinase 4 (GRK4). We review here research in this field that has provided several translational opportunities, ranging from diagnostic tests to gene therapy, such as (1) a test in renal proximal tubule cells isolated from the urine of humans that may determine the salt-sensitive phenotype by analyzing the recruitment of dopamine D1 receptors to the plasma membrane; (2) the presence of common GRK4 gene variants that are not only associated with hypertension but may also be predictive of the response to antihypertensive therapy; (3) genetic testing for polymorphisms of the dopamine D2 receptor that may be associated with hypertension and inverse salt sensitivity and may increase the susceptibility to chronic kidney disease because of loss of the antioxidant and anti-inflammatory effects of the renal dopamine D2 receptor, and (4) in vivo renal selective amelioration of renal tubular genetic defects by a gene transfer approach, using adeno-associated viral vectors introduced to the kidney by retrograde ureteral infusion.