Abstract
Simple SummaryThe renal sodium chloride cotransporter (NCC) plays an important role in the total body electrolyte balance and blood pressure control. The regulation of this protein by the actin cytoskeleton has not been thoroughly studied. Here, we investigate a novel association between the actin cytoskeleton protein filamin A and the NCC using a mouse cellular model and in the native kidney. Our results show for the first time that the disruption of the actin cytoskeleton reduces NCC activity and filamin A plays an essential role in NCC protein expression in cells of the distal convoluted tubule. We further show that the pharmacological inhibition of the Ca2+/calmodulin dependent protein kinase II (CAMKII) augments NCC protein expression. These results introduce a new mechanism for the regulation of the NCC.The thiazide-sensitive sodium chloride cotransporter (NCC) in the distal convoluted tubule is responsible for reabsorbing up to one-tenth of the total filtered load of sodium in the kidney. The actin cytoskeleton is thought to regulate various transport proteins in the kidney but the regulation of the NCC by the actin cytoskeleton is largely unknown. Here, we identify a direct interaction between the NCC and the cytoskeletal protein filamin A in mouse distal convoluted tubule (mDCT15) cells and in the native kidney. We show that the disruption of the actin cytoskeleton by two different mechanisms downregulates NCC activity. As filamin A is a substrate of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), we investigate the physiological significance of CaMKII inhibition on NCC luminal membrane protein expression and NCC activity in mDCT15 cells. The pharmacological inhibition of CaMKII with the compound KN93 increases the active form of the NCC (phospho-NCC) at the luminal membrane and also increases NCC activity in mDCT15 cells. These data suggest that the interaction between the NCC and filamin A is dependent on CaMKII activity, which may serve as a feedback mechanism to maintain basal levels of NCC activity in the distal nephron.
Highlights
This article is an open access articleHypertension is a growing public health concern worldwide and is a major risk factor for increasing morbidity and mortality from strokes, cardiovascular diseases, and renal failure [1]
In order to determine whether the activity of the renal NCC was affected by disruptions in the actin cytoskeleton, we treated Mouse DCT15 cells (mDCT15) cells with two different chemical disruptors of the actin cytoskeleton, latrunculin B and cytochalasin D
We examined whether filamin A directly interacts with the NCC
Summary
This article is an open access articleHypertension is a growing public health concern worldwide and is a major risk factor for increasing morbidity and mortality from strokes, cardiovascular diseases, and renal failure [1]. Hypertension affects more than 40% of adults older than the age of 25 years and nearly one-third of the adult population in the United States [2] It has been estimated distributed under the terms and conditions of the Creative Commons. The distal convoluted tubule (DCT) is part of the aldosterone-sensitive distal nephron and it plays a critical role in maintaining the total body sodium balance and blood pressure control [5]. It is the shortest segment in the nephron, it plays a crucial role in a variety of homeostatic processes including sodium chloride reabsorption, potassium secretion, and calcium handling. The abnormal expression and activity of the NCC have been implicated in blood pressure and electrolyte imbalances including
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