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Insulin production and signaling in renal tubules of Drosophila is under control of tachykinin-related peptide and regulates stress resistance.

Söderberg JA, Birse RT, Nässel DR - PLoS ONE (2011)

Bottom Line: Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype.Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation.Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, Stockholm University, Stockholm, Sweden.

ABSTRACT
The insulin-signaling pathway is evolutionarily conserved in animals and regulates growth, reproduction, metabolic homeostasis, stress resistance and life span. In Drosophila seven insulin-like peptides (DILP1-7) are known, some of which are produced in the brain, others in fat body or intestine. Here we show that DILP5 is expressed in principal cells of the renal tubules of Drosophila and affects survival at stress. Renal (Malpighian) tubules regulate water and ion homeostasis, but also play roles in immune responses and oxidative stress. We investigated the control of DILP5 signaling in the renal tubules by Drosophila tachykinin peptide (DTK) and its receptor DTKR during desiccative, nutritional and oxidative stress. The DILP5 levels in principal cells of the tubules are affected by stress and manipulations of DTKR expression in the same cells. Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype. Thus, stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP5 signaling. Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation. Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone.

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Manipulations of S6 kinase in principal cells alters survival during stress.A. Over expression of S6 Kinase (S6K) in principal cells by the transgene C324/UAS-S6K leads to abbreviated lifespan at desiccation by 10–20% (P<0.001 and P<0.002 to the two controls respectively; Log rank test; n = 106–118 for the different genotypes). B. Expression of a dominant negative form of S6K with C324 driven UAS-S6KDN extends lifespan at desiccation by about 10% (P<0.001 to both controls; n = 107–115).
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pone-0019866-g006: Manipulations of S6 kinase in principal cells alters survival during stress.A. Over expression of S6 Kinase (S6K) in principal cells by the transgene C324/UAS-S6K leads to abbreviated lifespan at desiccation by 10–20% (P<0.001 and P<0.002 to the two controls respectively; Log rank test; n = 106–118 for the different genotypes). B. Expression of a dominant negative form of S6K with C324 driven UAS-S6KDN extends lifespan at desiccation by about 10% (P<0.001 to both controls; n = 107–115).

Mentions: To monitor the effects of interference with signaling downstream of the dInR we targeted S6K (ribosomal S6 kinase) in principal cells. We over-expressed wild type S6K with the transgene C324-Gal4/UAS-S6K, which should phenocopy increased insulin signaling [44], [45], [46] in the principal cells. Indeed, this leads to a reduced survival at desiccation (Fig. 6A; p<0.005 and p<0.001 versus the two controls). Inactivation of S6K signaling by expression of a dominant negative construct (UAS-S6KDN) in principal cells produces the opposite phenotype (Fig. 6B; p<0.001). We also targeted the translational repressor 4E-BP (eukaryotic translation initiation factor 4E binding protein; Thor), known to play a role in lifespan extension at dietary restriction, starvation and oxidative stress in Drosophila [47], [48]. Expression of a mutant form of 4E-BP with increased activity (4E-BPLL) in principal cells resulted in increased lifespan at desiccation (Fig. S7A; p<0.01), whereas over expression of the wild type form did not significantly affect lifespan (Fig. S7B).


Insulin production and signaling in renal tubules of Drosophila is under control of tachykinin-related peptide and regulates stress resistance.

Söderberg JA, Birse RT, Nässel DR - PLoS ONE (2011)

Manipulations of S6 kinase in principal cells alters survival during stress.A. Over expression of S6 Kinase (S6K) in principal cells by the transgene C324/UAS-S6K leads to abbreviated lifespan at desiccation by 10–20% (P<0.001 and P<0.002 to the two controls respectively; Log rank test; n = 106–118 for the different genotypes). B. Expression of a dominant negative form of S6K with C324 driven UAS-S6KDN extends lifespan at desiccation by about 10% (P<0.001 to both controls; n = 107–115).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3091884&req=5

pone-0019866-g006: Manipulations of S6 kinase in principal cells alters survival during stress.A. Over expression of S6 Kinase (S6K) in principal cells by the transgene C324/UAS-S6K leads to abbreviated lifespan at desiccation by 10–20% (P<0.001 and P<0.002 to the two controls respectively; Log rank test; n = 106–118 for the different genotypes). B. Expression of a dominant negative form of S6K with C324 driven UAS-S6KDN extends lifespan at desiccation by about 10% (P<0.001 to both controls; n = 107–115).
Mentions: To monitor the effects of interference with signaling downstream of the dInR we targeted S6K (ribosomal S6 kinase) in principal cells. We over-expressed wild type S6K with the transgene C324-Gal4/UAS-S6K, which should phenocopy increased insulin signaling [44], [45], [46] in the principal cells. Indeed, this leads to a reduced survival at desiccation (Fig. 6A; p<0.005 and p<0.001 versus the two controls). Inactivation of S6K signaling by expression of a dominant negative construct (UAS-S6KDN) in principal cells produces the opposite phenotype (Fig. 6B; p<0.001). We also targeted the translational repressor 4E-BP (eukaryotic translation initiation factor 4E binding protein; Thor), known to play a role in lifespan extension at dietary restriction, starvation and oxidative stress in Drosophila [47], [48]. Expression of a mutant form of 4E-BP with increased activity (4E-BPLL) in principal cells resulted in increased lifespan at desiccation (Fig. S7A; p<0.01), whereas over expression of the wild type form did not significantly affect lifespan (Fig. S7B).

Bottom Line: Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype.Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation.Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, Stockholm University, Stockholm, Sweden.

ABSTRACT
The insulin-signaling pathway is evolutionarily conserved in animals and regulates growth, reproduction, metabolic homeostasis, stress resistance and life span. In Drosophila seven insulin-like peptides (DILP1-7) are known, some of which are produced in the brain, others in fat body or intestine. Here we show that DILP5 is expressed in principal cells of the renal tubules of Drosophila and affects survival at stress. Renal (Malpighian) tubules regulate water and ion homeostasis, but also play roles in immune responses and oxidative stress. We investigated the control of DILP5 signaling in the renal tubules by Drosophila tachykinin peptide (DTK) and its receptor DTKR during desiccative, nutritional and oxidative stress. The DILP5 levels in principal cells of the tubules are affected by stress and manipulations of DTKR expression in the same cells. Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted in increased survival at either stress, whereas over-expression of these components produced the opposite phenotype. Thus, stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP5 signaling. Manipulations of S6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locally on tubules, possibly in oxidative stress regulation. Our findings are the first to demonstrate DILP signaling originating in the renal tubules and that this signaling is under control of stress-induced release of peptide hormone.

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