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Metabolic alterations serve a significant role in the pathogenesis of kidney disease. Long non‑coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) is a known regulator of podocyte health and mitochondrial biogenesis. Although TUG1 protects against podocyte loss in models of diabetic nephropathy, it is unknown if urinary TUG1 expression is associated with clinical and histopathological findings in non‑diabetic patients diagnosed with glomeru‑ lonephritides. In the present study, the expression of TUG1, podocyte‑specific markers (nephrin and podocin) and mito‑ chondrial biogenesis‑associated mRNAs (transcription factor A mitochondrial, cytochrome C oxidase subunit 5A and peroxisome proliferator‑activated receptor γ coactivator 1α) were examined in urinary sediment of non‑diabetic patients with biopsy‑confirmed glomerulonephritides and healthy controls. Urinary expression of TUG1 was significantly lower in patients with glomerulonephritides, particularly those diagnosed with Focal Segmental Glomerulosclerosis (FSGS). Furthermore, TUG1 levels were associated with urinary expression of podocyte‑specific markers and mRNAs associ‑ ated with mitochondrial biogenesis. Loss of TUG1 expression in urinary sediment was strongly associated with FSGS, high‑ lighting the potential of this lncRNA and its mitochondrial biogenesis‑associated targets as non‑invasive biomarkers of assessing podocytopathy. [ABSTRACT FROM AUTHOR]

Background/Aims: Studies on the biological actions of vasoinhibins have focused mainly on endothelial cells. However, there is incipient knowledge about how vasoinhibins affect the nervous system, even if the target cells and mechanisms of action involved in these effects are unknown. Methods: In order to determine if neurons are direct targets of vasoinhibins, we examined cellular outcomes and the intracellular pathways involved in the neuronal actions of vasoinhibins using newborn rat dorsal root ganglion (DRG) neurons as a model system. Results: Vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) treatment for 48 h resulted in neurite outgrowth stimulation in both DRG cultured explants and isolated primary sensory neurons. Interestingly, a recombinant vasoinhibin containing the first 123 amino acids of human prolactin antagonized the VEGF- and NGF-induced stimulation of neurite outgrowth. Vasoinhibin significantly reduced the density of neurites in DRG explants and obliterated neuritogenesis in isolated DRG neurons in primary culture, supporting a direct neuronal effect of vasoinhibin. In cultures of isolated DRG cells, virtually all β3-tubulin-labeled cells express TrkA, and the majority of these cells also express VEGFR2. Short-term VEGF or NGF treatment of DRG explants resulted in increased ERK1/2 and AKT phosphorylation, whereas incubation of DRG with the combination of either VEGF or NGF together with vasoinhibin resulted in blunted VEGF- or NGF-induced phosphorylation of both ERK1/2 and AKT. Conclusion: Our results show that primary sensory neurons are direct targets of vasoinhibin, and suggest that vasoinhibin inhibition of neurite outgrowth involves the disruption of ERK and AKT phosphorylation cascades. [ABSTRACT FROM AUTHOR]

The K+ -Cl- cotransporters (KCC1-KCC4) encompass a branch of the SLC12 family of electro-neutral cation-coupled chloride cotransporters that translocate ions out of the cell to regulate various factors, including cell volume and intracellular chloride concentration, among others. L-WNK1 is an ubiquitously expressed kinase that is activated in response to osmotic stress and intracellular chloride depletion, and it is implicated in two distinct hereditary syndromes: the renal disease pseudohypoaldosteronism type II (PHAII) and the neurological disease hereditary sensory neuropathy 2 (HSN2). The effect of L-WNK1 on KCC activity is unknown. Using Xenopus laevis oocytes and HEK-293 cells, we show that the activation of KCCs by cell swelling was prevented by L-WNK1 coexpression. In contrast, the activity of the N+ -K+ -2Cl- cotransporter NKCC1 was remarkably increased with L-WNK1 co-expression. The negative effect of L-WNK1 on the KCCs is kinase dependent. Elimination of the STE20 proline-alanine rich kinase (SPAK)/oxidative stress-responsive kinase (OSR1) binding site or the HQ motif required for the WNK-WNK interaction prevented the effect of L-WNK1 on KCCs, suggesting a required interaction between L-WNK1 molecules and SPAK. Together, our data support that NKCC1 and KCCs are coordinately regulated by L-WNK1 isoforms. [ABSTRACT FROM AUTHOR]

K+-Cl- cotransporter (KCC) isoforms 3 (KCC3) and 4 (KCC4) are expressed at the basolateral membrane of proximal convoluted tubule cells, and KCC4 is present in the basolateral membrane of the thick ascending loop of Henle's limb and α-intercalated cells of the collecting duct. Little is known, however, about the physiological roles of these transporters in the kidney. We evaluated KCC3 and KCC4 mRNA and protein expression levels and intrarenal distribution in male Wistar rats or C57 mice under five experimental conditions: hyperglycemia after a single dose of streptozotocin, a low-salt diet, metabolic acidosis induced by ammonium chloride in drinking water, and low- or high-K+ diets. Both KCC3 mRNA and protein expression were increased during hyperglycemia in the renal cortex and at the basolateral membrane of proximal tubule cells but not with a low-salt diet or acidosis. In contrast, KCC4 protein expression was increased by a low-sodium diet in the whole kidney and by metabolic acidosis in the renal outer medulla, specifically at the basolateral membrane of α-intercalated cells. The increased protein expression of KCC4 by a low-salt diet was also observed in WNK4 knockout mice, suggesting that upregulation of KCC4 in these circumstances is not WNK4 dependent. No change in KCC3 or KCC4 protein expression was observed under low- or high-K+ diets. Our data are consistent with a role for KCC3 in the proximal tubule glucose reabsorption mechanism and for KCC4 in salt reabsorption of the thick ascending loop of Henle's loop and acid secretion of the collecting duct. [ABSTRACT FROM AUTHOR]

The K+:Cl- cotransporters or KCCs are membrane proteins that move K+ and Cl- ions across the membrane without changing the transmembrane potential. KCCs belong to the SLC12 (Solute Carrier Family 12) family of electroneutral cation-chloride cotransporters (CCC), and they are secondary active ion transporters because use the established gradients from the primary active transporter through the Na+/K+- ATPase. Although there are nine members identify in this family, up today only seven genes had been characterized. Among them are two loop diuretics-sensitive Na+:K+:2Clcotransporters (NKCC1/NKCC2), the thiazide-sensitive Na+:Cl- cotransporter (NCC), and finally the K+:Cl- cotransporters (KCC), encoded for at least four homologous genes (KCC1-KCC4), and from which there are many isoforms due to alternative splicing. KCC1 is a ubiquitous isoform, KCC3 and KCC4 isoforms are widely expressed, particularly in epithelial cells, while KCC2 is restricted to the central nervous system (CNS). All these cotransporters play an essential role in many physiological processes such as cell volume regulation, transepithelial salt transport and regulation of the intraneuronal chloride concentration. This review has the purpose to show briefly the molecular characteristics as well as the physiological importance and roles of the KCCs in several pathologies.