Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin 2.

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin 2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin.

Macrophage SPAK deletion limits a low potassium-induced kidney inflammatory program.

Inadequate dietary potassium (K) consumption is a significant contributor to poor cardiovascular outcomes. A diet with reduced K content has been shown to cause salt-sensitive increases in blood pressure. More recently, we have also shown that reductions in blood K can cause direct kidney injury, independent of dietary sodium (Na) content.

Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance.

Dietary potassium deficiency causes stimulation of sodium reabsorption leading to an increased risk in blood pressure elevation. The distal convoluted tubule (DCT) is the main rheostat linking plasma K levels to the activity of the Na-Cl cotransporter (NCC). This occurs through basolateral membrane potential sensing by inwardly rectifying K channels (Kir4.

Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.

The renal epithelium is sensitive to changes in blood potassium (K). We identify the basolateral K channel, Kir4.2, as a mediator of the proximal tubule response to K deficiency.

Kidney collecting duct-derived vasopressin is not essential for appropriate concentration or dilution of urine.

We have previously shown that kidney collecting ducts make vasopressin. However, the physiological role of collecting duct-derived vasopressin is uncertain. We hypothesized that collecting duct-derived vasopressin is required for the appropriate concentration of urine.

Rac1 promotes kidney collecting duct repair by mechanically coupling cell morphology to mitotic entry.

Prolonged obstruction of the ureter, which leads to injury of the kidney collecting ducts, results in permanent structural damage, while early reversal allows for repair. Cell structure is defined by the actin cytoskeleton, which is dynamically organized by small Rho guanosine triphosphatases (GTPases). In this study, we identified the Rho GTPase, Rac1, as a driver of postobstructive kidney collecting duct repair.

Epidermal growth factor receptor activation is essential for kidney fibrosis development.

Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated.

Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology.

Transporters of the solute carrier family 12 (SLC12) carry inorganic cations such as Na and/or K alongside Cl across the plasma membrane of cells. These tightly coupled, electroneutral, transporters are expressed in almost all tissues/organs in the body where they fulfil many critical functions. The family includes two key transporters participating in salt reabsorption in the kidney: the Na-K-2Cl cotransporter-2 (NKCC2), expressed in the loop of Henle, and the Na-Cl cotransporter (NCC), expressed in the distal convoluted tubule.

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.

High sodium intake does not worsen low potassium-induced kidney damage.

High sodium and low potassium intake have both been linked to poor cardiovascular health outcomes and increased mortality rates. A combination of the two is thought to be particularly detrimental. While mechanisms are multiple, the kidney is an important target of harmful effects and low potassium influences on both proximal and distal nephron segments are especially potent.

Bicarbonate is the primary inducer of KCC3a expression in renal cortical B-type intercalated cells.

A primary function of intercalated cells in the distal tubule of the kidney is to maintain pH homeostasis. For example, type B intercalated cells secrete bicarbonate largely through the action of the apical Cl/HCO exchanger, pendrin, which helps correct metabolic alkalosis. Since both the K-Cl cotransporter, KCC3a and pendrin colocalize to the apical region of type B and non-A, non-B intercalated cells and since both are upregulated in models of metabolic alkalosis, such as with dietary NaHCO loading, we raised the possibility that apical KCC3a facilitates pendrin-mediated bicarbonate secretion, such as through apical Cl recycling.

Insulin-regulated aminopeptidase is required for water excretion in response to acute hypotonic stress.

The objective of this study was to understand the response of mice lacking insulin-regulated aminopeptidase (IRAP) to an acute water load. For mammals to respond appropriately to acute water loading, vasopressin activity needs to decrease. IRAP degrades vasopressin in vivo.

Kir4.2 mediates proximal potassium effects on glutaminase activity and kidney injury.

Inadequate potassium (K) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K deficiency causes direct kidney injury.

Kidney collecting duct cells make vasopressin in response to NaCl-induced hypertonicity.

Vasopressin has traditionally been thought to be produced by the neurohypophyseal system and then released into the circulation where it regulates water homeostasis. The questions of whether vasopressin could be produced outside of the brain and if the kidney could be a source of vasopressin are raised by the syndrome of inappropriate antidiuretic hormone secretion (vasopressin). We found that mouse and human kidneys expressed vasopressin mRNA.

EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance.

Obesity and obesity-related health complications are increasing in prevalence. Adipose tissue from obese subjects has low-grade, chronic inflammation, leading to insulin resistance. Adipose tissue macrophages (ATMs) are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction.

KCC3a, a Strong Candidate Pathway for K Loss in Alkalemia.

Loss-of-function mutations in the human potassium chloride cotransporter-3 (KCC3) cause a hereditary motor sensory neuropathy associated with agenesis of the corpus callosum. While recapitulating the neuropathy, KCC3-knockout mice also exhibit high blood pressure. This phenotype is believed to have neurogenic and/or vascular origins.

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.

Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction.

Peripheral Insulin Resistance Is Associated with Copeptin in Patients with Chronic Kidney Disease.

Background: Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus.

Macrophage interferon regulatory factor 4 deletion ameliorates aristolochic acid nephropathy via reduced migration and increased apoptosis.

Aristolochic acid (AA) is the causative nephrotoxic alkaloid in AA nephropathy, which results in a tubulointerstitial fibrosis. AA causes direct proximal tubule damage as well as an influx of macrophages, although the role of macrophages in pathogenesis is poorly understood. Here, we demonstrate that AA directly stimulates migration, inflammation, and ROS production in macrophages ex vivo.

Myeloid cyclooxygenase-2/prostaglandin E2/E-type prostanoid receptor 4 promotes transcription factor MafB-dependent inflammatory resolution in acute kidney injury.

Following acute injury to the kidney, macrophages play an important role in recovery of functional and structural integrity, but organ fibrosis and progressive functional decline occur with incomplete recovery. Pro-resolving macrophages are characterized by increased cyclooxygenase 2 (COX-2) expression and this expression was selectively increased in kidney macrophages following injury and myeloid-specific COX-2 deletion inhibited recovery. Deletion of the myeloid prostaglandin E2 (PGE2) receptor, E-type prostanoid receptor 4 (EP4), mimicked effects seen with myeloid COX-2-/- deletion.

Rac1 promotes kidney collecting duct integrity by limiting actomyosin activity.

A polarized collecting duct (CD), formed from the branching ureteric bud (UB), is a prerequisite for an intact kidney. The small Rho GTPase Rac1 is critical for actin cytoskeletal regulation. We investigated the role of Rac1 in the kidney collecting system by selectively deleting it in mice at the initiation of UB development.