Targeting inerleukin-6 for renoprotection.

Sterile inflammation has been increasingly recognized as a hallmark of non-infectious kidney diseases. Induction of pro-inflammatory cytokines in injured kidney tissue promotes infiltration of immune cells serving to clear cell debris and facilitate tissue repair. However, excessive or prolonged inflammatory response has been associated with immune-mediated tissue damage, nephron loss, and development of renal fibrosis.

Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors.

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive.

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.

Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments.

Aim: 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 for cyclosporine A (CsA) as well as for the currently favored tacrolimus (Tac).

Metabolic effects of vasopressin in pathophysiology of diabetic kidney disease.

The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types.

Calcineurin inhibitors stimulate Kir4.1/Kir5.1 of the distal convoluted tubule to increase NaCl cotransporter.

We examine whether calcineurin or protein phosphatase 2B (PP2B) regulates the basolateral inwardly rectifying potassium channel Kir4.1/Kir5.1 in the distal convoluted tubule (DCT).

Studies in Zebrafish and Rat Models Support Dual Blockade of EP2 and EP4 (Prostaglandin E Receptors Type 2 and 4) for Renoprotection in Glomerular Hyperfiltration and Albuminuria.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E (PGE) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE receptor type 2) and EP4 (PGE receptor type 4) in GH.

Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model.

Aim: Perturbed calcium homeostasis limits life expectancy in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease occurs by loss-of-function mutations in CLDN16 or CLDN19 genes, causing impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). Only partial compensation takes place in the ensuing late distal convoluted tubule, connecting tubule, and collecting duct, where the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium-potassium exchanger (NCX1) mediate transcellular Ca reabsorption.

Combination of immune checkpoint inhibitors with radiation therapy in cancer: A hammer breaking the wall of resistance.

Immuno-oncology is an emerging field in the treatment of oncological diseases, that is based on recruitment of the host immune system to attack the tumor. Radiation exposure may help to unlock the potential of the immune activating agents by enhancing the antigen release and presentation, attraction of immunocompetent cells to the inflammation site, and eliminating the tumor cells by phagocytosis, thereby leading to an overall enhancement of the immune response. Numerous preclinical studies in mouse models of glioma, murine melanoma, extracranial cancer, or colorectal cancer have contributed to determination of the optimal radiotherapy fractionation, as well as the radio- and immunotherapy sequencing strategies for maximizing the antitumor activity of the treatment regimen.

Unrecognized role of claudin-10b in basolateral membrane infoldings of the thick ascending limb.

Claudin-10b is an important component of the tight junction in the thick ascending limb (TAL) of Henle's loop and allows paracellular sodium transport. In immunofluorescence stainings, claudin-10b-positive cells exhibited extensive extra staining of basolateral, column-like structures. The precise localization and function have so far remained elusive.

Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells.

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. CsA inhibits calcineurin by forming complexes with cyclophilins, whose chaperone function is essential for proteostasis.

Claudin-10a Deficiency Shifts Proximal Tubular Cl Permeability to Cation Selectivity Claudin-2 Redistribution.

Background: The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear.

Methods: To investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals.

Angiotensin II receptor blockade alleviates calcineurin inhibitor nephrotoxicity by restoring cyclooxygenase 2 expression in kidney cortex.

Aim: The use of calcineurin inhibitors such as cyclosporine A (CsA) for immunosuppression after solid organ transplantation is commonly limited by renal side effects. CsA-induced deterioration of glomerular filtration rate and sodium retention may be related to juxtaglomerular dysregulation as a result of suppressed cyclooxygenase 2 (COX-2) and stimulated renin biosynthesis. We tested whether CsA-induced COX-2 suppression is caused by hyperactive renin-angiotensin system (RAS) and whether RAS inhibition may alleviate the related side effects.

Can Molecular Biology Propose Reliable Biomarkers for Diagnosing Major Depression?

Background: Modern medicine has provided considerable knowledge of the pathophysiology of mental disorders at the body, systemic, organ and neurochemical levels of the biological organization of the body. Modern clinical diagnostics of depression have some problems, that is why psychiatric society makes use of diagnostics and taxonomy of different types of depression by implemention of modern molecular biomarkers in diagnostic procedures. But up to now, there are no reliable biomarkers of major depressive disorder (MDD) and other types of depression.

Calcium-Sensing Receptor and Regulation of WNK Kinases in the Kidney.

The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca levels including the control of parathyroid hormone release and regulation of the renal calcium handling.

P2X7 Receptor Stimulation Is Not Required for Oxalate Crystal-Induced Kidney Injury.

Oxalate crystal-induced renal inflammation is associated with progressive kidney failure due to activation of the NLRP3/CASP-1 inflammasome. It has been suggested previously that purinergic P2X7 receptor signaling is critical for crystal-induced inflammasome activation and renal injury. Therefore, we investigated the role of the P2X7 receptor in response to crystal-induced cytokine release, inflammation, and kidney failure using in vitro and in vivo models.

Hyperkalemia and blood pressure regulation.

Hypertension is common in the general population. Management of hypertensive patients at risk of hyperkalemia is challenging due to potential life-threatening complications such as cardiac arrest. Chronic hyperkalemia is often associated with impaired renal ability to excrete excessive potassium ions (K+).

WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia.

K deficiency stimulates renal salt reuptake via the Na-Cl cotransporter (NCC) of the distal convoluted tubule (DCT), thereby reducing K 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 of Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1). In K deficiency, WNKs and SPAK/OSR1 concentrate in spherical cytoplasmic domains in the DCT termed "WNK bodies," the significance of which is undetermined.

Vasopressin Increases Urinary Acidification V1a Receptors in Collecting Duct Intercalated Cells.

Background: Antagonists of the V1a vasopressin receptor (V1aR) are emerging as a strategy for slowing progression of CKD. Physiologically, V1aR signaling has been linked with acid-base homeostasis, but more detailed information is needed about renal V1aR distribution and function.

Methods: We used a new anti-V1aR antibody and high-resolution microscopy to investigate Va1R distribution in rodent and human kidneys.

Dynamic Modulation of Mouse Locus Coeruleus Neurons by Vasopressin 1a and 1b Receptors.

The locus coeruleus (LC) is a brainstem nucleus distinguished by its supply of noradrenaline throughout the central nervous system. Apart from modulating a range of brain functions, such as arousal, cognition and the stress response, LC neuronal excitability also corresponds to the activity of various peripheral systems, such as pelvic viscera and the cardiovascular system. Neurochemically diverse inputs set the tone for LC neuronal activity, which in turn modulates these adaptive physiological and behavioral responses essential for survival.

Patients with hypokalemia develop WNK bodies in the distal convoluted tubule of the kidney.

Hypokalemia contributes to the progression of chronic kidney disease, although a definitive pathophysiological theory to explain this remains to be established. K deficiency results in profound alterations in renal epithelial transport. These include an increase in salt reabsorption via the Na-Cl cotransporter (NCC) of the distal convoluted tubule (DCT), which minimizes electroneutral K loss in downstream nephron segments.

AMP-activated kinase is a regulator of fibroblast growth factor 23 production.

Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1.

A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling.

The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERα) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2.

Caveolin 1 Promotes Renal Water and Salt Reabsorption.

Caveolin-1 (Cav1) is essential for the formation of caveolae. Little is known about their functional role in the kidney. We tested the hypothesis that caveolae modulate renal salt and water reabsorption.

GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation.

Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit.