Lipides, Nutrition, Cancer
Intervenant : Dr Khalil El-Karoui
Endoplasmic reticulum stress and chronic kidney disease progression
Background: In chronic kidney disease (CKD), protein leakage from damaged glomeruli results in severe tubulointerstitial lesions which ultimately lead to end stage renal disease (1). Despite the fact that several molecular pathways have been involved in the deleterious effect of proteinuria, none of them has led to the development of efficient therapeutic strategies (2-3). By combining genetic and acquired models of proteinuria with in vitro studies, we demonstrated that the activation of ER stress and unfolded protein response (UPR) in tubular cells is a hallmark of proteinuric diseases. Mechanistically, we showed that albumin induces tubular UPR in a calcium-dependent manner. Furthermore, UPR induces tubular apoptosis by modulating the expression Lipocalin 2 (LCN2), a known mediator of CKD progression (4), via ATF4. Notably, Lcn2 gene inactivation protects proteinuric mice from tubulointerstitial lesions and mortality by decreasing ER stress-induced apoptosis. More importantly, we identified the 4-phenylbutyrate acid (PBA), a chemical chaperone already used in humans, as a potential pharmacological inhibitor of this pathway. In fact, we showed that PBA administration results in reduced ER stress, dampened LCN2 activation, decreased tubular lesions, and improved renal function in proteinuric mice. These results are relevant to human CKD, since LCN2 is increased in proteinuric patients (5). In conclusions, our study uncovers a novel molecular pathway involved in CKD progression and identifies a therapeutic strategy for preserving kidneys during proteinuria..
1. Remuzzi, G., Benigni, A. & Remuzzi, A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116, 288-96 (2006).
2. Zandi-Nejad, K., Eddy, A.A., Glassock, R.J. & Brenner, B.M. Why is proteinuria an ominous biomarker of progressive kidney disease? Kidney Int Suppl, S76-89 (2004).
3. Ruggenenti, P., Cravedi, P. & Remuzzi, G. Mechanisms and treatment of CKD. J Am Soc Nephrol 23, 1917-28 (2012).
4. Viau, A.,El Karoui K, et al. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest 120, 4065-4076 (2010).
5. El Karoui K, et al. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat Com 7, 10330 (2016)
Invitation: Carmen Garrido- UMR1231
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