ClC-Kb pore mutation disrupts glycosylation and triggers distal tubular remodeling.

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.

Independent regulation of Piezo1 activity by principal and intercalated cells of the collecting duct.

The renal collecting duct is continuously exposed to a wide spectrum of fluid flow rates and osmotic gradients. Expression of a mechanoactivated Piezo1 channel is the most prominent in the collecting duct. However, the status and regulation of Piezo1 in functionally distinct principal and intercalated cells (PCs and ICs) of the collecting duct remain to be determined.

TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium.

Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca ] homeostasis and flow-sensitive [Ca ] signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP-dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K intake modulates the rate of cystogenesis and mechanosensitive [Ca ] signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD).

of ClC-K2 Cl Channel in the Collecting Duct Intercalated Cells.

The renal collecting duct is known to play a critical role in many physiological processes, including systemic water-electrolyte homeostasis, acid-base balance, and the salt sensitivity of blood pressure. ClC-K2 (ClC-Kb in humans) is a Cl-permeable channel expressed on the basolateral membrane of several segments of the renal tubule, including the collecting duct intercalated cells. ClC-Kb mutations are causative for Bartters' syndrome type 3 manifested as hypotension, urinary salt wasting, and metabolic alkalosis.

ClC-K2 Cl channel allows identification of A- and B-type of intercalated cells in split-opened collecting ducts.

The collecting duct is a highly adaptive terminal part of the nephron, which is essential for maintaining systemic homeostasis. Principal and intercalated cells perform different physiological tasks and exhibit distinctive morphology. However, acid-secreting A- and base secreting B-type of intercalated cells cannot be easily separated in functional studies.

With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron.

Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K balance, in part, by orchestrating maxi K channel (BK)-dependent K secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca-permeable TRPV4 channel is essential for BK activation in the ASDN.

Angiotensin II increases activity of the ClC-K2 Cl channel in collecting duct intercalated cells by stimulating production of reactive oxygen species.

The renal collecting duct plays a critical role in setting urinary volume and composition, with principal cells transporting Na and K and intercalated cells mediating Cl reabsorption. Published evidence implies Angiotensin II (Ang II) is a potent regulator of the collecting duct apical transport systems in response to systemic volume depletion. However, virtually nothing is known about Ang II actions on the basolateral conductance of principal and intercalated cells.

Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion.

The diversity and near universal expression of G protein-coupled receptors (GPCR) reflects their involvement in most physiological processes. The GPCR superfamily is the largest in the human genome, and GPCRs are common pharmaceutical targets. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential.

Polymodal roles of TRPC3 channel in the kidney.

TRPC3 is a Ca-permeable cation channel commonly activated by the G-protein coupled receptors (GPCR) and mechanical distortion of the plasma membrane. TRPC3-mediated Ca influx has been implicated in a variety of signaling processes in both excitable and non-excitable cells. Kidneys play a commanding role in maintaining whole-body homeostasis and setting blood pressure.

PF-06869206 is a selective inhibitor of renal P transport: evidence from in vitro and in vivo studies.

Plasma phosphate (P) levels are tightly controlled, and elevated plasma P levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of P reabsorption: Na-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70-80% of P reabsorption. The aim of the present study was to determine the in vitro effects of a novel Npt2a inhibitor (PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a) mice.

Adenosine inhibits the basolateral Cl ClC-K2/b channel in collecting duct intercalated cells.

Adenosine plays an important role in various aspects of kidney physiology, but the specific targets and mechanisms of actions are not completely understood. The collecting duct has the highest expression of adenosine receptors, particularly adenosine A receptors (ARs). Interstitial adenosine levels are greatly increased up to a micromolar range in response to dietary salt loading.

TRPC3 determines osmosensitive [Ca2+]i signaling in the collecting duct and contributes to urinary concentration.

It is well-established that the kidney collecting duct (CD) plays a central role in regulation of systemic water homeostasis. Aquaporin 2 (AQP2)-dependent water reabsorption in the CD critically depends on the arginine vasopressin (AVP) antidiuretic input and the presence of a favorable osmotic gradient at the apical plasma membrane with tubular lumen being hypotonic compared to the cytosol. This osmotic difference creates a mechanical force leading to an increase in [Ca2+]i in CD cells.

Dietary K and Cl independently regulate basolateral conductance in principal and intercalated cells of the collecting duct.

The renal collecting duct contains two distinct cell types, principal and intercalated cells, expressing potassium K4.1/5.1 (KCNJ10/16) and chloride ClC-K2 (ClC-Kb in humans) channels on their basolateral membrane, respectively.

The renal TRPV4 channel is essential for adaptation to increased dietary potassium.

To maintain potassium homeostasis, kidneys exert flow-dependent potassium secretion to facilitate kaliuresis in response to elevated dietary potassium intake. This process involves stimulation of calcium-activated large conductance maxi-K (BK) channels in the distal nephron, namely the connecting tubule and the collecting duct. Recent evidence suggests that the TRPV4 channel is a critical determinant of flow-dependent intracellular calcium elevations in these segments of the renal tubule.