A5085820518- Ion Transport and Channel Regulation
- Electrolyte and hormonal disorders
- Neuroendocrine regulation and behavior
- Renal Transplantation Outcomes and Treatments
- Ion channel regulation and function
- Magnesium in Health and Disease
- Signaling Pathways in Disease
- Barrier Structure and Function Studies
- Pancreatic function and diabetes
- Renal and related cancers
- Adenosine and Purinergic Signaling
- Nitric Oxide and Endothelin Effects
- Organ Transplantation Techniques and Outcomes
- Potassium and Related Disorders
- Inflammatory mediators and NSAID effects
- Parathyroid Disorders and Treatments
- Oral and gingival health research
- Chronic Kidney Disease and Diabetes
- Caveolin-1 and cellular processes
- S100 Proteins and Annexins
- Drug Transport and Resistance Mechanisms
- Circadian rhythm and melatonin
- RNA Interference and Gene Delivery
- Orthopedic Surgery and Rehabilitation
- Elbow and Forearm Trauma Treatment
Charité - Universitätsmedizin Berlin
2015-2024
Sechenov University
2018-2024
Czech Academy of Sciences, Institute of Physiology
2024
Humboldt-Universität zu Berlin
2003-2019
Freie Universität Berlin
2019
Max Delbrück Center
2004
Active transport of NaCl across thick ascending limb (TAL) epithelium is accomplished by Na(+),K(+),2Cl(-) cotransporter (NKCC2). The activity NKCC2 determined vasopressin (AVP) or intracellular chloride concentration and includes its amino-terminal phosphorylation. Co-expressed Tamm-Horsfall protein (THP) has been proposed to interact with NKCC2. We hypothesized that THP modulates in TAL. THP-deficient mice (THP(-/-)) showed an increased abundance located subapical vesicles (+47% compared...
In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ion transport. thick ascending limb (TAL) Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular routes. TAL salt transport maintains concentrating ability kidney generates a transepithelial voltage that drives calcium magnesium. Thus, functionality depends strongly on properties pathway. To elucidate role protein claudin-10 in...
Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or substrate adaptor kelch-like (KLHL3). Disease-associated CUL3 abrogate kinase degradation cells, but it not clear how mutant forms of promote stability. Here, we demonstrated that an FHHt-causing (CUL3 Δ403–459) only retains ability to bind and ubiquitylate kinases KLHL3 also more heavily neddylated activated than WT CUL3....
Significance Hypertension, one of the most common morbidity factors worldwide, is caused mostly by a deregulation salt transport kidney, but underlying mechanisms remain elusive. The serine-threonine kinase With No lysine (K) 1 (WNK1) has been identified as regulator ion in distal nephron, because its mutations cause Familial Hyperkalemic Hypertension (FHHt), rare form human hypertension. We generated mouse model WNK1-FHHt that fully recapitulates disease and studied changes expression Na +...
The lateral habenula (LHb) has a key role in integrating variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types neuronal within LHb coordinate physiological motivational states. Here, we report type medial division (LHbM) male rats that distinguished by: (1) molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) estrogen receptor (Esr1/ERα) expression, at both mRNA protein levels, as well vesicular...
The thick ascending limb (TAL) of Henle's loop drives paracellular Na+, Ca2+, and Mg2+ reabsorption via the tight junction (TJ). TJ is composed claudins that consist four transmembrane segments, two extracellular segments (ECS1 -2), one intracellular loop. Claudins interact within same (cis) opposing (trans) plasma membranes. Cldn10b, -16, -19 facilitate cation in TAL, their absence leads to a severe disturbance renal ion homeostasis. We combined electrophysiological measurements on...
The Tamm-Horsfall protein (THP; uromodulin), the dominant in normal urine, is produced exclusively thick ascending limb of Henle's loop. THP mutations are associated with disease; however, physiological role remains obscure. We generated gene-deficient mice (THP -/-) and compared them wild-type (WT) mice. -/- displayed anatomically kidneys. Steady-state electrolyte handling was not different between strains. Creatinine clearance 63% lower than WT (P < 0.05). Sucrose loading induced no...
In renal epithelia, vasopressin influences salt and water transport, chiefly via V(2) receptors (V(2)Rs) linked to adenylyl cyclase. A combination of vasopressin-induced effects along several distinct portions the nephron collecting duct system may help balance net antidiuresis in cortex medulla. Previous studies intrarenal distribution V(2)Rs have been inconclusive with respect segment- cell-type-related V(2)R expression. Our study therefore aimed present a high-resolution analysis mRNA...
Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in renal collecting duct to maintain homeostasis of body water. AVP binds vasopressin V2 receptors (V2R), increasing cAMP, which promotes redistribution AQP2 from intracellular vesicles into plasma membrane. cAMP also increases transcription, but whether altered degradation protein levels is not well understood. Here, elevation increased within 30 minutes primary inner medullary (IMCD) cells, human embryonic kidney...
Tamm-Horsfall glycoprotein (THGP) or Uromodulin is a membrane protein exclusively expressed along the thick ascending limb (TAL) and early distal convoluted tubule (DCT) of nephron. Mutations in THGP encoding gene result Familial Juvenile Hyperuricemic Nephropathy (FJHN), Medullary Cystic Kidney Disease type 2 (MCKD-2), Glomerulocystic (GCKD). The physicochemical biological properties have been studied extensively, but its physiological function TAL remains obscure. We performed yeast...
Vasopressin influences salt and water transport in renal epithelia. This is coordinated by the combined action of V 2 receptor-mediated effects along distinct nephron segments. Modulation NaCl reabsorption vasopressin has been established loop Henle, but its role distal convoluted tubule (DCT), an effective site for fine regulation urinary electrolyte composition target thiazide diuretics, largely unknown. The Na + -Cl − cotransporter (NCC) DCT activated luminal trafficking phosphorylation...
Activation of the Na+-K+-2Cl−-cotransporter (NKCC2) and Na+-Cl−-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine serine residues, but kinase pathways that mediate this action are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich (SPAK) oxidative stress responsive (OSR1), can phosphorylate cotransporters directly. In process, a full-length SPAK variant OSR1 interact with truncated variant, which...
We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously to be negative regulator of NCC, it has been postulated converts positive regulator. Here, we ask whether aldosterone requires NCC if their effects are additive. To do so, infused vehicle or in adrenalectomized rats also received receptor blocker losartan. In presence losartan, still capable increasing total...
The tight junction proteins claudin-2 and claudin-10a form paracellular cation anion channels, respectively, are expressed in the proximal tubule. However, physiologic role of kidney has been unclear.To investigate claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western immunofluorescence staining, analyzed urine serum wild-type animals. We also used electrophysiologic studies to functionality isolated tubules, studied compensatory...
Introduction. The development of a bioreactor providing three-dimensional network interwoven capillary membranes with integrated oxygenation and decentralized mass exchange enables the culture primary human liver cells from discarded donor organs for extracorporeal support. Methods. Primary were isolated 54 (donor age 56.7±13.2 years). Between 2.8×1010 6.4×1010 parenchymal (PC) cocultured nonparenchymal (NPC) same organ in bioreactors (n=36). metabolic activity was regularly determined...
Renal reabsorption of inorganic phosphate is mediated by the type IIa sodium cotransporter (NaPi-IIa) proximal tubule. Changes in renal handling are mainly attributable to altered NaPi-IIa brush border membrane (BBM) expression. Parathyroid hormone (PTH) induces inactivation endocytic retrieval and degradation. The key elements triggering this process not clear date. Megalin serves as a receptor for endocytosis multiple ligands coexpressed with Investigated was role megalin regulation steady...
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...
Current immunosuppressive strategies in organ transplantation rely on calcineurin inhibitors cyclosporine A (CsA) or tacrolimus (Tac). Both drugs are nephrotoxic, but CsA has been associated with greater renal damage than Tac. inhibits by forming complexes cyclophilins, whose chaperone function is essential for proteostasis. We hypothesized that stronger toxicity of may be related to suppression cyclophilins ensuing endoplasmic reticulum (ER) stress and unfolded protein response (UPR) kidney...
Calcineurin inhibitors (CNIs) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects contribute to allograft injury. Renal parenchymal lesions occur cyclosporine A (CsA) as well currently favored tacrolimus (Tac). We aimed study whether chronic CsA and Tac exposures, before reaching irreversible damage, affect renal compartments differentially related pathogenic mechanisms can be...
Apical bumetanide-sensitive Na + -K -2Cl − cotransporter (NKCC2), the kidney-specific member of a cation-chloride superfamily, is an integral membrane protein responsible for transepithelial reabsorption NaCl. The role NKCC2 essential renal volume regulation. Vasopressin (AVP) controls surface expression in cells thick ascending limb loop Henle (TAL). We found that 40–70% Triton X-100-insoluble was present cholesterol-enriched lipid rafts (LR) rat kidney and cultured TAL cells. related -Cl...
Background: The oxidative stress-responsive kinase 1 (OSR1) participates in the WNK-(with no K) dependent regulation of renal salt excretion and blood pressure. Little is known, however, about role OSR1 further transport systems. present study analyzed effect on NaPiIIa, major tubular phosphate transporter. Methods: Immunohistochemistry confocal microscopy were employed to determine localization NaPiIIa. To elucidate OSR NaPiIIa activity, cRNA encoding was injected into Xenopus oocytes with...