Going with the flow: New insights regarding flow induced K secretion in the distal nephron.

K secretion in the distal nephron has a critical role in K homeostasis and is the primary route by which K is lost from the body. Renal K secretion is enhanced by increases in dietary K intake and by increases in tubular flow rate in the distal nephron. This review addresses new and important insights regarding the mechanisms underlying flow-induced K secretion (FIKS).

Epithelial Na + Channel Activation after Bile Duct Ligation with Mineralocorticoid Receptor Blockade.

Key Points: Bile acids activate the epithelial Na channel (ENaC), which may lead to subsequent fluid retention in liver disease. Bile duct ligation with spironolactone increased ENaC-dependent Na and fluid retention without hormone-linked increased ENaC abundance. Counteracting bile acid ENaC activation may be effective for treating fluid retention in liver disease.

alternative splicing in mouse kidney: regulation during development and by dietary K intake.

The pore-forming α-subunit of the large-conductance K (BK) channel is encoded by a single gene, BK channel-mediated K secretion in the kidney is crucial for overall renal K homeostasis in both physiological and pathological conditions. BK channels achieve phenotypic diversity by various mechanisms, including substantial exon rearrangements at seven major alternative splicing sites. However, alternative splicing in the kidney has not been characterized.

Influence of proteolytic cleavage of ENaC's γ subunit upon Na and K handling.

The epithelial Na channel (ENaC) γ subunit is essential for homeostasis of Na, K, and body fluid. Dual γ subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (P), in vitro. Cleavage proximal to the tract occurs at a furin recognition sequence (RKRR, in the mouse γ subunit).

Cannabinoid receptor type 1 activation causes a water diuresis by inducing an acute central diabetes insipidus in mice.

Cannabis and synthetic cannabinoid consumption are increasing worldwide. Cannabis contains numerous phytocannabinoids that act on the G protein-coupled cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 expressed throughout the body, including the kidney. Essentially every organ, including the kidney, produces endocannabinoids, which are endogenous ligands to these receptors.

PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion.

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity.

Proteolytic Cleavage of the ENaC γ Subunit - Impact Upon Na and K Handling.

The ENaC gamma subunit is essential for homeostasis of Na , K , and body fluid. Dual subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (P ), . Cleavage proximal to the tract occurs at a furin recognition sequence ( RKRR in mouse).

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice.

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms.

Navigating the kidney organoid: insights into assessment and enhancement of nephron function.

Kidney organoids are three-dimensional structures generated from pluripotent stem cells (PSCs) that are capable of recapitulating the major structures of mammalian kidneys. As this technology is expected to be a promising tool for studying renal biology, drug discovery, and regenerative medicine, the functional capacity of kidney organoids has emerged as a critical question in the field. Kidney organoids produced using several protocols harbor key structures of native kidneys.

Functional maturation of kidney organoid tubules: PIEZO1-mediated Ca signaling.

Kidney organoids cultured on adherent matrices in the presence of superfusate flow generate vascular networks and exhibit more mature podocyte and tubular compartments compared with static controls (Homan KA, Gupta N, Kroll KT, Kolesky DB, Skylar-Scott M, Miyoshi T, Mau D, Valerius MT, Ferrante T, Bonventre JV, Lewis JA, Morizane R. 16: 255-262, 2019; Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH. 526: 564-568, 2015.

Live functional assays reveal longitudinal maturation of transepithelial transport in kidney organoids.

Kidney organoids derived from hPSCs have opened new opportunities to develop kidney models for preclinical studies and immunocompatible kidney tissues for regeneration. Organoids resemble native nephrons that consist of filtration units and tubules, yet little is known about the functional capacity of these organoid structures. Transcriptomic analyses provide insight into maturation and transporter activities that represent kidney functions.

A reference tissue atlas for the human kidney.

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells.

L-WNK1 is required for BK channel activation in intercalated cells.

Large-conductance K (BK) channels expressed in intercalated cells (ICs) in the aldosterone-sensitive distal nephron (ASDN) mediate flow-induced K secretion. In the ASDN of mice and rabbits, IC BK channel expression and activity increase with a high-K diet. In cell culture, the long isoform of with-no-lysine kinase 1 (L-WNK1) increases BK channel expression and activity.

Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis.

KCNJ16 encodes K5.1 and acts in combination with K4.1, encoded by KCNJ10, to form an inwardly rectifying K channel expressed at the basolateral membrane of epithelial cells in the distal nephron.

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index.

Background: For the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function.

Methods: Our study included 453 mother-child pairs participating in the PROGRESS birth cohort.

Exosomal miRNAs in urine associated with children's cardiorenal parameters: a cross-sectional study.

The authors sought to examine associations between urinary exosomal miRNAs (exo-miRs), emerging biomarkers of renal health, and cardiorenal outcomes in early childhood. The authors extracted exo-miRs in urine from 88 healthy Mexican children aged 4-6 years. The authors measured associations between 193 exo-miRs and cardiorenal outcomes: systolic/diastolic blood pressure, estimated glomerular filtration rate and urinary sodium and potassium levels.

Intercalated cell BKα subunit is required for flow-induced K+ secretion.

BK channels are expressed in intercalated cells (ICs) and principal cells (PCs) in the cortical collecting duct (CCD) of the mammalian kidney and have been proposed to be responsible for flow-induced K+ secretion (FIKS) and K+ adaptation. To examine the IC-specific role of BK channels, we generated a mouse with targeted disruption of the pore-forming BK α subunit (BKα) in ICs (IC-BKα-KO). Whole cell charybdotoxin-sensitive (ChTX-sensitive) K+ currents were readily detected in control ICs but largely absent in ICs of IC-BKα-KO mice.

Efficacy and safety of inhaled once-daily low-dose indacaterol acetate/mometasone furoate in patients with inadequately controlled asthma: Phase III randomised QUARTZ study findings.

Background: Global initiative for asthma (GINA) 2019 recommends adding a long-acting β-agonist (LABA) to an inhaled corticosteroid (ICS) as a maintenance controller therapy in patients with inadequately controlled asthma. Indacaterol acetate (IND, a LABA) in combination with mometasone furoate (MF, an ICS) is under development for the treatment of these patients.

Objective: This phase III QUARTZ was a multicentre, randomised, double-blind, double-dummy and parallel-group study to assess the efficacy and safety of low-dose IND/MF 150/80 μg once daily (o.

Length of gestation and birth weight are associated with indices of combined kidney biomarkers in early childhood.

Infants born prematurely or with low birth weights are more susceptible to kidney dysfunction throughout their lives. Multiple proteins measured in urine are noninvasive biomarkers of subclinical kidney damage, but few studies have examined the joint effects of multiple biomarkers. We conducted an exploratory study of 103 children in the Programing Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) longitudinal birth cohort, and measured nine proteins selected a priori in banked spot urine samples collected at ages 4-6.

Expression and distribution of PIEZO1 in the mouse urinary tract.

The proper function of the organs that make up the urinary tract (kidneys, ureters, bladder, and urethra) depends on their ability to sense and respond to mechanical forces, including shear stress and wall tension. However, we have limited understanding of the mechanosensors that function in these organs and the tissue sites in which these molecules are expressed. Possible candidates include stretch-activated PIEZO channels (PIEZO1 and PIEZO2), which have been implicated in mechanically regulated body functions including touch sensation, proprioception, lung inflation, and blood pressure regulation.

Prenatal lead exposure modifies the effect of shorter gestation on increased blood pressure in children.

Background: High blood pressure (BP) in childhood is frequently renal in origin and a risk factor for adult hypertension and cardiovascular disease. Shorter gestations are a known risk factor for increased BP in adults and children, due in part to a nephron deficit in children born preterm. As nephrogenesis is incomplete until 36 weeks gestation, prenatal lead exposure occurring during a susceptible period of renal development may contribute to programming for later life renal disease.

Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992.

The inward rectifier potassium (Kir) channel Kir4.1 () carries out important physiologic roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness.