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Article Dans Une Revue Scientific Reports Année : 2020

Collecting duct cells show differential retinoic acid responses to acute versus chronic kidney injury stimuli

Résumé

Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury. In RARE-LacZ mice, Adriamycin-induced heavy albuminuria was associated with reduced RA/RAR activity in CD cells. In cultured CD cells, RA/RAR activity was repressed by acetylcholine, albumin, aldosterone, angiotensin II, high glucose, cisplatin and lipopolysaccharide, but was induced by aristolochic acid I, calcitonin gene-related peptide, endothelin-1, gentamicin, norepinephrine and vasopressin. Compared with age-matched normal human CD cells, CD-derived renal cystic epithelial cells from patients with autosomal recessive polycystic kidney disease (ARPKD) had significantly lower RA/ RAR activity. Synthetic RAR agonist RA-568 was more potent than RA in rescuing RA/RAR activity repressed by albumin, high glucose, angiotensin II, aldosterone, cisplatin and lipopolysaccharide. Hence, RA/RAR in CD cells is a convergence point of regulation by neurotransmitters and mediators of kidney injury, and may be a novel therapeutic target. Acute kidney injury (AKI) is an abrupt renal insult followed by sudden decline of kidney functions 1,2 ; chronic kidney disease (CKD) is a long-term condition where the kidneys do not work effectively, resulting in chronic loss of renal functions 3,4. AKI occurs in 10-15% hospitalised patients and approximately 50% patients in intensive care, and is associated with high mortality 2 ; affecting 8-16% of the world's population 3,4 , CKD was the 12th most common cause of mortality and caused 4.6% of deaths globally in 2017 5. If this rising prevalence of CKD continues, it is predicted that CKD will become a top-5 cause of mortality worldwide by 2040 6. AKI and CKD are not distinct disease entities but rather are closely interconnected syndromes 7. Despite some shared aetiologies, risk factors and mechanisms, the pathophysiology of AKI and CKD can be quite different. Although AKI may be caused by systemic, vascular, glomerular and tubular diseases, the core pathophysiology of AKI is often predominated by tubulointerstitial injury 2. On the other hand, although a wide range of aetiologies may all cause CKD, the latter is most often a glomerular disease 4. However, regardless of the primary aetiologies of CKD, tubulointerstitial injury plays a crucial role in CKD progression to end-stage kidney disease 8. Thus, it is critical to investigate the mechanism of tubulointerstitial injury, which is as yet poorly understood. What we open
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Dates et versions

hal-02989672 , version 1 (05-11-2020)

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Alexandros Papadimitriou, Paola Romagnani, Maria Lucia Angelotti, Mazhar Noor, Jonathan Corcoran, et al.. Collecting duct cells show differential retinoic acid responses to acute versus chronic kidney injury stimuli. Scientific Reports, 2020, 10 (1), pp.1-12. ⟨10.1038/s41598-020-73099-9⟩. ⟨hal-02989672⟩
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