End-stage renal disease (ESRD) is a medical condition resulting from chronic kidney disease (CKD), which affects millions of persons worldwide and constitutes a major public health problem and economic challenge. Despite considerable progress, numerous challenges remain related to the mechanisms, the prevention and the cure of CKD, with immediate consequences for the patients in terms of mortality, morbidity and cost to society. The renal medicine field needs to improve the current knowledge of the molecular processes that are critical for renal disease establishment and progression, and to accelerate the translation of basic science discoveries in the clinical field in terms of both early diagnostic and therapeutic strategies. We are willing to provide mechanistic insights into how the injured kidney activates adaptive responses to stress at the cellular level that would lead to CKD from in vitro cell models to genetically engineered murine models, transferring their clinical consequences to large-prospective human cohorts.
Acute Kidney Injury is associated with micro-environmental alterations and homeostasis disturbances, forcing cells to activate biological processes leading to profound metabolic reprogramming, which promotes cell survival in the injured milieu and eliminates stressors. In turn, disease reflects the inability of adaptive responses to restore tissue homeostasis. Kidneys have to cope with a wide array of insults that translate into elementary stressors at the cellular level (e.g., nutrient starvation, hypoxia, oxidative stress, inflammatory stress, and proteostasis disturbances). Adaptive responses to these stresses are often evolutionarily conserved molecular systems that primarily aim to eradicate or reduce stress intensity and promote metabolic reprogramming to maintain cellular homeostasis and other vital functions. Molecular modules sense microenvironmental fluctuations in nutrients, oxygen, and temperature, as well as disordered intracellular fluctuations, such as the accumulation of unfolded proteins and energy (ATP) shortage, among others.
These modules then transduce signals that will fuel metabolic reprogramming to maintain basal functions, while adapting the cell to the new environmental conditions. In addition to cellular decisions of life and death, these adaptive responses also participate in building communication networks that shape the stressed cell microenvironment, generally in a paracrine manner, leading to the activation of preemptive responses in cells that have not yet been subjected to the stress and to the production of alarm signals. Therefore, adaptive stress responses pathways are likely critical for tissue remodeling, as they shape the endogenous repair and scarring equilibrium in tissues and therefore significantly impact the functional outcomes of the injured kidney, ultimately leading to CKD. In addition, these molecular reprogramming circuitries and cellular adaptive responses occur very early after the initiation of AKI, well before cell death and the engagement of the maladaptive repair process. Thus, the detection of their activation constitutes an opportunity for an early diagnosis of ongoing tissue injury. Hence, characterizing the molecular mechanisms underlying the cellular responses to acute stress and their structural and functional consequences at the tissue level is crucial for the development of preventive and therapeutic strategies in renal medicine.
There is now clear evidence that ER stress or parts of the UPR that, for instance, target epithelial cells actively participate in the development of AKI and CKD, and we are currently developing a research program designed to demonstrate that the UPR, engaged upon acute tissue injury, is critical for tissue remodeling and therefore significantly impacts the functional outcomes of the injured kidney.
In summary, our projects have the goal of filling the gap between basic science and applied biomedical research and providing clinicians with accessible tools for the early prediction of CKD evolution, offering them the possibility to better personalize clinical management and treatment.
·Chemically based transmissible ER stress protocols are unsuitable to study cell-to-cell UPR transmission. Bignon Y, Poindessous V, Rampoldi L, Haldys V, Pallet N. Biochem J. 2020 Oct 30;477(20):4037-4051
The cellular prion protein is a stress protein secreted by renal tubular cells and a urinary marker of kidney injury. Bignon Y, Poindessous V, Lazareth H, Passet B, Vilotte JL, Djouadi F, Mouillet-Richard S, Pallet N. Cell Death Dis. 2020 Apr 17;11(4):243
Endoplasmic reticulum stress and kidney dysfunction. Gallazzini M, Pallet N. Biol Cell. 2018 Sep;110(9):205-216. doi: 10.1111/boc.201800019.
Real-Time and Non-invasive Monitoring of the Activation of the IRE1α-XBP1 Pathway in Individuals with Hemodynamic Impairment. Fohlen B, Tavernier Q, Huynh TM, Caradeuc C, Le Corre D, Bertho G, Cholley B, Pallet N. EBioMedicine. 2018 Jan;27:284-292.
A Comparative Study of the Predictive Values of Urinary Acute Kidney Injury Markers Angiogenin and Kidney Injury Molecule 1 for the Outcomes of Kidney Allografts. Tavernier Q, Tinel C, Rabant M, Morin L, Anglicheau D, Pallet N. Transplant Direct. 2017 Aug 16;3(9):e204.
he Diagnosis-Wide Landscape of Hospital-Acquired AKI. Jannot AS, Burgun A, Thervet E, Pallet N. Clin J Am Soc Nephrol. 2017 Jun 7;12(6):874-884.
Tavernier Q, Mami I, Rabant M, Karras A, Laurent-Puig P, Chevet E, Thervet E, Anglicheau D, Pallet N. Urinary Angiogenin Reflects the Magnitude of Kidney Injury at the Infrahistologic Level. J Am Soc Nephrol. 2016 Jul 19. pii: ASN.2016020218.
Mami I, Tavernier Q, Bouvier N, Aboukamis R, Desbuissons G, Rabant M, Poindessous V, Laurent-Puig P, Beaune P, Tharaux PL, Thervet E, Chevet E, Anglicheau D, Pallet N. A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney. J Am Soc Nephrol. 2016 Sep ; 27(9)2670-83.
Mami I, Pallet N. Transfer RNA fragmentation and protein translation dynamics in the course of kidney injury. RNA Biol. 2015 Oct 29:
Mami I, Bouvier N, El Karoui K, Gallazzini M, Rabant M, Laurent-Puig P, Li S, Tharaux PL, Beaune P, Thervet E, Chevet E, Hu GF, Pallet N. Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury. J Am Soc Nephrol. 2016 Mar ;27(3) : 863-76.
Fougeray S, Pallet N. Mechanisms and biological functions of autophagy in diseased and ageing kidneys. Nat Rev Nephrol. 2015 Jan;11(1):34-45.