Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy

Thati Madhusudhan; Hongjie Wang; Wei Dong; Sanchita Ghosh; Fabian Bock; Veera Raghavan Thangapandi; Satish Ranjan; Juliane Wolter; Shrey Kohli; Khurrum Shahzad; Florian Heidel; Martin Krueger; Vedat Schwenger; Marcus J. Moeller; Thomas Kalinski; Jochen Reiser; Triantafyllos Chavakis; Berend Isermann

doi:10.1038/ncomms7496

Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy

Thati Madhusudhan, Hongjie Wang, Wei Dong, Sanchita Ghosh, Fabian Bock, Veera Raghavan Thangapandi, Satish Ranjan, Juliane Wolter, Shrey Kohli, Khurrum Shahzad, Florian Heidel, Martin Krueger, Vedat Schwenger, Marcus J. Moeller, Thomas Kalinski, Jochen Reiser, Triantafyllos Chavakis, Berend Isermann

Research output: Contribution to journal › Article › peer-review

Abstract

Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85Î± or p85Î 2 impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85Î± and p85Î 2 is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.

Original language	English (US)
Article number	6496
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7496
State	Published - Mar 10 2015
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Madhusudhan, T., Wang, H., Dong, W., Ghosh, S., Bock, F., Thangapandi, V. R., Ranjan, S., Wolter, J., Kohli, S., Shahzad, K., Heidel, F., Krueger, M., Schwenger, V., Moeller, M. J., Kalinski, T., Reiser, J., Chavakis, T., & Isermann, B. (2015). Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nature communications, 6, Article 6496. https://doi.org/10.1038/ncomms7496

Madhusudhan, T, Wang, H, Dong, W, Ghosh, S, Bock, F, Thangapandi, VR, Ranjan, S, Wolter, J, Kohli, S, Shahzad, K, Heidel, F, Krueger, M, Schwenger, V, Moeller, MJ, Kalinski, T, Reiser, J, Chavakis, T & Isermann, B 2015, 'Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy', Nature communications, vol. 6, 6496. https://doi.org/10.1038/ncomms7496

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title = "Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy",

abstract = "Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85{\^I}± or p85{\^I} 2 impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85{\^I}± and p85{\^I} 2 is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.",

author = "Thati Madhusudhan and Hongjie Wang and Wei Dong and Sanchita Ghosh and Fabian Bock and Thangapandi, {Veera Raghavan} and Satish Ranjan and Juliane Wolter and Shrey Kohli and Khurrum Shahzad and Florian Heidel and Martin Krueger and Vedat Schwenger and Moeller, {Marcus J.} and Thomas Kalinski and Jochen Reiser and Triantafyllos Chavakis and Berend Isermann",

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doi = "10.1038/ncomms7496",

language = "English (US)",

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AU - Madhusudhan, Thati

AU - Wang, Hongjie

AU - Dong, Wei

AU - Ghosh, Sanchita

AU - Bock, Fabian

AU - Thangapandi, Veera Raghavan

AU - Ranjan, Satish

AU - Wolter, Juliane

AU - Kohli, Shrey

AU - Shahzad, Khurrum

AU - Heidel, Florian

AU - Krueger, Martin

AU - Schwenger, Vedat

AU - Moeller, Marcus J.

AU - Kalinski, Thomas

AU - Reiser, Jochen

AU - Chavakis, Triantafyllos

AU - Isermann, Berend

PY - 2015/3/10

Y1 - 2015/3/10

N2 - Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85Î± or p85Î 2 impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85Î± and p85Î 2 is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.

AB - Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85Î± or p85Î 2 impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85Î± and p85Î 2 is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.

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Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy

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