NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway.

The With No lysine (WNK) kinases regulate processes such as cell volume and epithelial ion transport through the modulation of Cation Chloride Cotransporters such as the NaCl cotransporter, NCC, present in the distal convoluted tubule (DCT) of the kidney. Recently, the interaction of WNKs with Nuclear Receptor Binding Protein 1 (NRBP1) and Transforming Growth Factor β-Stimulated Clone 22 Domain (TSC22D) proteins was reported. Here we explored the effect of NRBP1 and TSC22Ds on WNK signaling in vitro and in the DCT.

Mechanistic Differences between Torsemide and Furosemide.

Key Points: Oral torsemide was not superior to furosemide in measures of renal tubular delivery or duration of action. A dose equivalence of approximately 40 mg oral furosemide:10 mg oral torsemide resulted in similar natriuresis. The two-fold higher doses of torsemide did not improve fluid status due to the kidney’s compensation.

Klotho is highly expressed in the chief sites of regulated potassium secretion, and it is stimulated by potassium intake.

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K secretion channel (ROMK) and stimulates urinary K secretion, we explored if Klotho protein is regulated by dietary K and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice.

Potassium-Switch Signaling Pathway Dictates Acute Blood Pressure Response to Dietary Potassium.

Background: Potassium (K)-deficient diets, typical of modern processed foods, increase blood pressure (BP) and NaCl sensitivity. A K-dependent signaling pathway in the kidney distal convoluted tubule, coined the K switch, that couples extracellular K sensing to activation of the thiazide-sensitive NaCl cotransporter (NCC) and NaCl retention has been implicated, but causality has not been established.

Methods: To test the hypothesis that small, physiological changes in plasma K (P) are translated to BP through the switch pathway, a genetic approach was used to activate the downstream switch kinase, SPAK (SPS1-related proline/alanine-rich kinase), within the distal convoluted tubule.

Enriched Single-Nucleus RNA-Sequencing Reveals Unique Attributes of Distal Convoluted Tubule Cells.

Significance Statement: High-resolution single-nucleus RNA-sequencing data indicate a clear separation between primary sites of calcium and magnesium handling within distal convoluted tubule (DCT). Both DCT1 and DCT2 express Slc12a3, but these subsegments serve distinctive functions, with more abundant magnesium-handling genes along DCT1 and more calcium-handling genes along DCT2. The data also provide insight into the plasticity of the distal nephron-collecting duct junction, formed from cells of separate embryonic origins.

Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na Channel (ENaC).

Background: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively.

Modifying Dietary Sodium and Potassium Intake: An End to the 'Salt Wars'?

Excessive salt intake raises blood pressure, but the implications of this observation for human health have remained contentious. It has also been recognized for many years that potassium intake may mitigate the effects of salt intake on blood pressure and possibly on outcomes such as stroke. Recent large randomized intervention trials have provided strong support for the benefits of replacing salt (NaCl) with salt substitute (75% NaCl, 25% KCl) on hard outcomes, including stroke.

Randomized Trial on the Effect of Oral Potassium Chloride Supplementation on the Thiazide-Sensitive Sodium Chloride Cotransporter in Healthy Adults.

Introduction: The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake.

Methods: Healthy adults maintained on a high sodium (∼4.

Geographic and Temporal Trends in COVID-Associated Acute Kidney Injury in the National COVID Cohort Collaborative.

Background: AKI is associated with mortality in patients hospitalized with coronavirus disease 2019 (COVID-19); however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied.

Methods: Electronic health record data were obtained from 53 health systems in the United States in the National COVID Cohort Collaborative. We selected hospitalized adults diagnosed with COVID-19 between March 6, 2020, and January 6, 2022.

COVID-19-associated AKI in hospitalized US patients: incidence, temporal trends, geographical distribution, risk factors and mortality.

Background: Acute kidney injury (AKI) is associated with mortality in patients hospitalized with COVID-19, however, its incidence, geographic distribution, and temporal trends since the start of the pandemic are understudied.

Methods: Electronic health record data were obtained from 53 health systems in the United States (US) in the National COVID Cohort Collaborative (N3C). We selected hospitalized adults diagnosed with COVID-19 between March 6th, 2020, and January 6th, 2022.

COP9 signalosome deletion promotes renal injury and distal convoluted tubule remodeling.

Cullin-RING ligases are a family of E3 ubiquitin ligases that control cellular processes through regulated degradation. Cullin 3 targets with-no-lysine kinase 4 (WNK4), a kinase that activates the Na-Cl cotransporter (NCC), the main pathway for Na reabsorption in the distal convoluted tubule (DCT). Mutations in the cullin 3 gene lead to familial hyperkalemic hypertension by increasing WNK4 abundance.

Mineralocorticoid Receptor Antagonists Cause Natriuresis in the Absence of Aldosterone.

Background: MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). 11βHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct.

Diuretics in States of Volume Overload: Core Curriculum 2022.

Volume overload, defined as excess total body sodium and water with expansion of extracellular fluid volume, characterizes common disorders such as congestive heart failure, end-stage liver disease, chronic kidney disease, and nephrotic syndrome. Diuretics are the cornerstone of therapy for volume overload and comprise several classes whose mechanisms of action, pharmacokinetics, indications, and adverse effects are essential principles of nephrology. Loop diuretics are typically the first-line treatment in the management of hypervolemia, with additional drug classes indicated in cases of diuretic resistance and electrolyte or acid-base disorders.