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Tamma G.,University of Bari | Tamma G.,Italian National Institute of Biosystems and Biostructures | Valenti G.,University of Bari | Valenti G.,Italian National Institute of Biosystems and Biostructures | Valenti G.,Centro Of Eccellenza Of Genomica In Campo Biomedico Ed Agrario Cegba
Antioxidants and Redox Signaling | Year: 2016

Significance: Reactive oxygen species (ROS) have long been considered as toxic derivatives of aerobic metabolism displaying a harmful effect to living cells. Deregulation of redox homeostasis and production of excessive free radicals may contribute to the pathogenesis of kidney diseases. In line, oxidative stress increases in patients with renal dysfunctions due to a general increase of ROS paralleled by impaired antioxidant ability. Recent Advances: Emerging evidence revealed that physiologically, ROS can act as signaling molecules interplaying with several transduction pathways such as proliferation, differentiation, and apoptosis. ROS can exert signaling functions by modulating, at different layers, protein oxidation since proteins have "cysteine switches" that can be reversibly reduced or oxidized, supporting the dynamic signaling regulation function. In this scenario, S-glutathionylation is a posttranslational modification involved in oxidative cellular response. Critical Issues: Although it is widely accepted that renal dysfunctions are often associated with altered redox signaling, the relative role of S-glutathionylation on the pathogenesis of specific renal diseases remains unclear and needs further investigations. In this review, we discuss the impact of ROS in renal health and diseases and the role of selective S-glutathionylation proteins potentially relevant to renal physiology. Future Directions: The paucity of studies linking the reversible protein glutathionylation with specific renal disorders remains unmet. The growing number of S-glutathionylated proteins indicates that this is a fascinating area of research. In this respect, further studies on the association of reversible glutathionylation with renal diseases, characterized by oxidative stress, may be useful to develop new pharmacological molecules targeting protein S-glutathionylation. © Mary Ann Liebert, Inc. 2016.

Carmosino M.,Yale University | Carmosino M.,University of Bari | Rizzo F.,University of Bari | Procino G.,University of Bari | And 7 more authors.
Molecular Biology of the Cell | Year: 2010

The renal-specific Na +-K +-2Cl - cotransporter (NKCC2) is the major salt transport pathway of the apical membrane of the mammalian thick ascending limb of Henle's loop. Here, we analyze the role of the tetraspan protein myelin and lymphocytes-associated protein (MAL)/VIP17 in the regulation of NKCC2. We demonstrated that 1) NKCC2 and MAL/VIP17 colocalize and coimmunoprecipitate in Lilly Laboratories cell porcine kidney cells (LLC-PK1) as well as in rat kidney medullae, 2) a 150-amino acid stretch of NKCC2 C-terminal tail is involved in the interaction with MAL/VIP17, 3) MAL/VIP17 increases the cell surface retention of NKCC2 by attenuating its internalization, and 4) this coincides with an increase in cotransporter phosphorylation. Interestingly, overexpression of MAL/VIP17 in the kidney of transgenic mice results in cysts formation in distal nephron structures consistent with the hypothesis that MAL/VIP17 plays an important role in apical sorting or in maintaining the stability of the apical membrane. The NKCC2 expressed in these mice was highly glycosylated and phosphorylated, suggesting that MAL/VIP17 also is involved in the stabilization of NKCC2 at the apical membrane in vivo. Thus, the involvement of MAL/VIP17 in the activation and surface expression of NKCC2 could play an important role in the regulated absorption of Na + and Cl - in the kidney. © 2010 M. Carmosino et al.

Tamma G.,University of Bari | Lasorsa D.,University of Bari | Ranieri M.,University of Bari | Mastrofrancesco L.,University of Bari | And 3 more authors.
Cellular Physiology and Biochemistry | Year: 2011

Aquaporin-2 (AQP2) increases the water permeability of renal collecting ducts in response to vasopressin. Vasopressin stimulation is accompanied by a profound remodeling of actin cytoskeleton whose dynamics are regulated by crosstalk between intracellular and extracellular signals. Here, we report that AQP2 contains a conserved RGD domain in its external C-loop. Co-immunoprecipitation experiments demonstrated that AQP2 binds integrin β1 in renal tissue and in MCD4 cells. To investigate the role of this interaction on AQP2 trafficking, cells were exposed to synthetic RGD-containing peptides, GRGDNP or GRGDSP, able to bind certain integrins. Incubation with these peptides increased the membrane expression of AQP2 in the absence of hormonal stimulation as assessed by confocal analysis and cell surface biotinylation. To identify the signals underlying the effects of peptides on AQP2 trafficking, some possible intracellular messengers were evaluated. Exposure of MCD4 cells to GRGDNP increased intracellular cAMP as assessed by FRET studies while GRGDSP increased intracellular calcium concentration. Taken together, these data propose integrins as new players controlling the cellular localization of AQP2, via two distinct signal transduction pathways dependent on cAMP and calcium respectively. Copyright © 2011 S. Karger AG, Basel.

Procino G.,University of Bari | Barbieri C.,University of Bari | Carmosino M.,University of Bari | Tamma G.,University of Bari | And 8 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2011

X-linked nephrogenic diabetes insipidus (XNDI), a severe pathological condition characterized by greatly impaired urine-concentrating ability of the kidney, is caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene. The lack of functional V2Rs prevents vasopressin-induced shuttling of aquaporin-2 (AQP2) water channels to the apical plasma membrane of kidney collecting duct principal cells, thus promoting water reabsorption from urine to the interstitium. At present, no specific pharmacological therapy exists for the treatment of XNDI. We have previously reported that the cholesterol-lowering drug lovastatin increases AQP2 membrane expression in renal cells in vitro. Here we report the novel finding that fluvastatin, another member of the statins family, greatly increases kidney water reabsorption in vivo in mice in a vasopressin-independent fashion. Consistent with this observation, fluvastatin is able to increase AQP2 membrane expression in the collecting duct of treated mice. Additional in vivo and in vitro experiments indicate that these effects of fluvastatin are most likely caused by fluvastatin-dependent changes in the prenylation status of key proteins regulating AQP2 trafficking in collecting duct cells. We identified members of the Rho and Rab families of proteins as possible candidates whose reduced prenylation might result in the accumulation of AQP2 at the plasma membrane. In conclusion, these results strongly suggest that fluvastatin, or other drugs of the statin family, may prove useful in the therapy of XNDI. © 2011 Springer-Verlag.

Procino G.,University of Bari | Mastrofrancesco L.,University of Bari | Sallustio F.,University of Bari | Costantino V.,University of Bari | And 7 more authors.
Cellular Physiology and Biochemistry | Year: 2011

We screened human kidney-derived multipotent CD133+/CD24+ ARPCs for the possible expression of all 13 aquaporin isoforms cloned in humans. Interestingly, we found that ARPCs expressed both AQP5 mRNA and mature protein. This novel finding prompted us to investigate the presence of AQP5 in situ in kidney. We report here the novel finding that AQP5 is expressed in human, rat and mouse kidney at the apical membrane of type-B intercalated cells. AQP5 is expressed in the renal cortex and completely absent from the medulla. Immunocytochemical analysis using segment-and cell type-specific markers unambiguously indicated that AQP5 is expressed throughout the collecting system at the apical membrane of type-B intercalated cells, where it co-localizes with pendrin. No basolateral AQPs were detected in type-B intercalated cells, suggesting that AQP5 is unlikely to be involved in the net trans-epithelial water reabsorption occurring in the distal tubule. An intriguing hypothesis is that AQP5 may serve an osmosensor for the composition of the fluid coming from the thick ascending limb. Future studies will unravel the physiological role of AQP5 in the kidney. Copyright © 2011 S. Karger AG, Basel.

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