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) p85α or p85β impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85α and p85β 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.
Highlights
Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive endoplasmic reticulum (ER) signalling in podocytes remain unknown
activating transcription factor-6 (ATF6), activating transcription factor-4 (ATF4) and spliced X-box binding protein-1 (sXBP1), unveils a previously unrecognized role of insulin and the unfolded protein response (UPR) in Diabetic nephropathy (DN). These data establish that a maladaptive ER response, which is characterized by a disparate regulation of the tripartite-UPR, is causally linked to glomerular cell dysfunction and DN
Signalling via the XBP1 branch of the UPR is required for an adaptive ER response in DN, while genetic disruption or functional inactivation of this pathway in murine models of type 1 diabetes mellitus and type 2 diabetes mellitus promotes a maladaptive UPR
Summary
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. The UPR is a complex, yet highly coordinated programme, aiming to restore ER homeostasis either through proper folding of misfolded proteins via chaperons or degradation of these proteins[6] While this adaptive process is frequently beneficial in acute diseases, prolonged or persistent activation of the UPR may be detrimental in chronic diseases. Recent studies shed light on a selective transactivation mechanism of the IRE1/XBP1 pathway, operating independently of canonical IRE1a activation, in particular, interaction of p85 with sXBP1 promotes its nuclear translocation and activation[17,18,19]. Understanding the mechanisms through which the three branches of the UPR are regulated in DN may provide insights into the mechanisms of maladaptive versus adaptive UPR responses in DN and lay ground for novel therapeutic targets[20]
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