A5024997942- Ion Transport and Channel Regulation
- Ion channel regulation and function
- Magnesium in Health and Disease
- Cancer, Hypoxia, and Metabolism
- ATP Synthase and ATPases Research
- Electrolyte and hormonal disorders
- Hormonal Regulation and Hypertension
- Renal and related cancers
- Ubiquitin and proteasome pathways
- Renal function and acid-base balance
- Potassium and Related Disorders
- Aldose Reductase and Taurine
- Pancreatic function and diabetes
- Mitochondrial Function and Pathology
- Microbial metabolism and enzyme function
- Suicide and Self-Harm Studies
- Diet, Metabolism, and Disease
- Genomics, phytochemicals, and oxidative stress
- Resilience and Mental Health
- Cardiac electrophysiology and arrhythmias
- Genetic Syndromes and Imprinting
- Regulation of Appetite and Obesity
- Endoplasmic Reticulum Stress and Disease
- Open Education and E-Learning
- Genetics and Neurodevelopmental Disorders
Oregon Health & Science University
2016-2024
University of Portland
2021-2023
Oregon Health and Science University Hospital
2023
University of Nebraska Medical Center
2011-2015
Max Planck Institute for Heart and Lung Research
2015
University of Nebraska at Omaha
2011
K+ deficiency stimulates renal salt reuptake via the Na+-Cl- cotransporter (NCC) of distal convoluted tubule (DCT), thereby reducing losses in downstream nephron segments while increasing NaCl retention and blood pressure. NCC activation is mediated by a kinase cascade involving with no lysine (WNK) kinases upstream Ste20-related proline-alanine-rich (SPAK) oxidative stress-responsive kinase-1 (OSR1). In deficiency, WNKs SPAK/OSR1 concentrate spherical cytoplasmic domains DCT termed "WNK...
In the distal nephron, large-conductance Ca-activated K (BK) channel, comprised of a pore-forming-α (BK-α) and BK-β4 subunit, promotes excretion when mice are maintained on high-K alkaline diet (HK-alk). We examined whether acid-base status regulate apical membrane expression BK-α in cortical (CCD) medullary collecting ducts (MCD) using immunohistochemical analysis (IHC) Western blot. With use IHC, acontrol localized mostly cytoplasmically intercalated cells (IC) CCD perinuclear region both...
With no lysine kinase 4 (WNK4) is essential to activate the thiazide-sensitive NaCl cotransporter (NCC) along distal convoluted tubule, an effect central phenotype of familial hyperkalemic hypertension. Although effects on potassium and sodium channels connecting collecting tubules have also been documented, WNK4 typically believed little role in modulating chloride reabsorption thick ascending limb loop Henle. Yet wnk4-/- mice (knockout lacking WNK4) do not demonstrate hypocalciuria typical...
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 DCT2 express Slc12a3, but these subsegments serve distinctive functions, with more abundant magnesium-handling genes along calcium-handling DCT2. The also provide insight into the plasticity nephron-collecting duct junction, formed from cells separate embryonic origins. By...
Increased flow in the distal nephron induces K secretion through large-conductance, calcium-activated channel (BK), which is primarily expressed intercalated cells (IC). Since also increases ATP release from IC, we hypothesized that purinergic signaling has a role shear stress (τ; 10 dynes/cm(2)) -induced, BK-dependent, efflux. We found μM led to increased IC Ca concentration, was significantly reduced presence of P(2) receptor blocker suramin or calcium-free buffer. produced BK-dependent...
A low Na, high K diet (LNaHK) is associated with a rate of cardiovascular (CV) disease in many societies. Part the benefit LNaHK relies on its diuretic effects; however, role aldosterone (aldo) diuresis not understood. mice exhibit an increase renal secretion that dependent large, Ca-activated channel, (BK-α accessory BK-β4; BK-α/β4). We hypothesized aldo causes osmotic by increasing BK-α/β4-mediated mice. found plasma concentration (P[aldo]) was elevated 10-fold compared control (Con)...
Significance Statement Familial hyperkalemic hypertension (FHHt) results from inappropriate activation of the Na + Cl – cotransporter (NCC). Causative mutations have been identified in gene encoding Cullin3 (CUL3). with substrate binding adaptor Kelch-like 3 (KLHL3) forms an E3 ubiquitin ligase that mediates degradation NCC regulatory kinases. The mechanism by which mutant CUL3 causes FHHt is unclear, but lower abundance and KLHL3 proteins loss to regulator JAB1 implicated. Using several...
The renal cation cotransporters NCC and NKCC2 are activated following phosphorylation mediated by the WNK4-SPAK/OSR1 pathway. While disruption of this pathway strongly affects activity, effects on activity unclear since commonly used phospho-NKCC2 antibody was recently reported to cross-react with phospho-NCC in mice C57BL/6 background. Using a new specific for C57BL/6, we show that inhibition or activation only mildly phosphorylation.
Familial hyperkalemic hypertension is caused by mutations in with-no-lysine kinases (WNKs) or proteins that mediate their degradation, kelch-like 3 (KLHL3) and cullin (CUL3). Although the mechanisms which WNK KLHL3 cause disease are now clear, effects of disease-causing CUL3Δ403–459 mutation remain controversial. Possible mechanisms, including hyperneddylation, altered ubiquitin ligase activity, decreased association with COP9 signalosome (CSN), increased degradation have all been...
Background The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 (CUL3 Δ 9) bind normally the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. 9 also caused increased degradation of CUL3-WNK substrate adaptor kelch-like (KLHL3). Here, we sought determine how defective CSN action contributes phenotype. Methods Pax8/LC1 mouse...
Ca-activated K channels (BK), which are stimulated by high distal nephron flow, utilized during high-K conditions to remove excess K. Because BK predominantly reside with BK-β4 in acid/base-transporting intercalated cells (IC), we determined whether knockout mice (β4KO) exhibit deficient excretion when consuming a alkaline diet (HK-alk) vs. chloride (HK-Cl). When wild type (WT) were placed on HK-alk, but not HK-Cl, renal expression increased (Western blot). WT and β4KO plasma concentration...
The gene SLC4A5 encodes the Na(+)-HCO3 (-) cotransporter electrogenic 2, which is located in distal nephron. Genetically deleting 2 (knockout) causes Na(+)-retention and hypertension, a phenotype that diminished with alkali loading. We performed experiments acid-loaded mice determined whether overactive epithelial Na(+) channels (ENaC) or Na(+)-Cl(-) retention hypertension knockout. In untreated mice, mean arterial pressure was higher knockout, compared wild-type (WT); however, treatment...
Cre-lox technology has revolutionized research in renal physiology by allowing site-specific genetic recombination individual nephron segments. The distal convoluted tubule (DCT), consisting of distinct early (DCT1) and late (DCT2) segments, plays a central role Na + K homeostasis. only established Cre line targeting the DCT is Pvalb-Cre, which limited noninducibility, activity along DCT1 only, neurons. Here, we report characterization first specific to entire DCT. CRISPR/Cas9 was used...
In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. present study, we report that a mouse model lacking electrogenic Na + -HCO 3 − cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. expression was identified in connecting tubule (CNT) wild-type mice, and its significantly increased loading. KO mice did have when on standard diet. However, loading, exhibited complete features dRTA, characterized by...
Cullin-RING ligases are a family of E3 ubiquitin that control cellular processes through regulated degradation. Cullin 3 targets with-no-lysine kinase 4 (WNK4), activates the Na+-Cl- cotransporter (NCC), main pathway for Na+ reabsorption in distal convoluted tubule (DCT). Mutations cullin gene lead to familial hyperkalemic hypertension by increasing WNK4 abundance. The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) regulates activity cullin-RING removing ubiquitin-like protein...
Mutations in the ubiquitin ligase scaffold protein cullin 3 (CUL3) cause disease familial hyperkalemic hypertension (FHHt). We recently reported that kidney, aberrant mutant CUL3 (CUL3-Δ9) activity lowers abundance of CUL3-Δ9 and Kelch-like 3, substrate adaptor for with-no-lysine kinase 4 (WNK4) this is mechanistically important. However, whether exerts additional effects on other targets may alter renal function unclear. Here, we sought to determine 1) expression can rescue phenotype...
Abstract Background The distal convoluted tubule (DCT) comprises two subsegments, DCT1 and DCT2, with different functional molecular characteristics. distinction between these segments, however, has been controversial. Methods To understand the heterogeneity within DCT population better clarity, we enriched for nuclei by using a mouse line combining “Isolation of Nuclei TAgged in specific Cell Types” NCC (sodium chloride cotransporter)-driven inducible Cre recombinase. We sorted...