TEAM LEADER : Pierre-Louis Tharaux and Eric Camerer
Mail : pierre-louis.tharaux/or/eric.camerer@inserm.fr
PHONE :
THARAUX: +33 6 89 50 29 48;
CAMERER: +33 1 53 98 80 48
Localisation :
Tharaux lab: 2nd floor, room 219
Camerer lab: 3rd floor, room 361
DOCTORAL SCHOOL : Ecole Doctorale Bio Sorbonne Paris Cité (BioSPC)
Our team consists of three groups, two in basic and one in clinical research: the Tharaux group studies the role of cell communications in pathologies that arise secondary to glomerular capillary dysfunctions or cause them. The Camerer group studies functions of G protein-coupled receptors (GPCRs) in vascular development and disease. We have a common interest in how local signalling crosstalk regulate vascular integrity and how the loss of vascular integrity exacerbates inflammatory diseases, and we both use genetic and pharmacological tools to address these questions in mouse models.
We closely work with the Department of Nephrology at the Hôpital Européen Georges-Pompidou and the Department of Internal Medicine at Hôpital Cochin, Paris, on translational and clinical aspects. Our main scientific goals are to 1. Identify mechanisms of (peri)vascular signalling in development and disease, 2. Improve our understanding of the pathogenesis of immune-mediated and metabolic vascular and glomerular diseases (primarily focal segmental glomerulosclerosis (FSGS), crescentic rapidly progressive glomerulonephritis (RPGN), diabetic retinopathy and kidney disease), 3. Identify the roles of immune cells in sickle cell vasculopathy and nephropathy.
Rapidly progressive crescentic glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS) are severe kidney diseases responsible for irreversible renal failure, which is also a major risk factor for cardiovascular mortality. RPGN can even result in a loss of kidney function within days or weeks.
Despite the aggressiveness of immunosuppressive protocols applied, treatments against RPGN have limited effectiveness. Similarly, there is no approved, specific treatment for FSGS. The Tharaux’s group identified druggable pathways and markers of pathogenic glomerular epithelial cells (GEC).
Our findings reinforce this paradigm that “activation” of resident glomerular cells play a key role in disease progression and extend the concept by examining interactions between surrounding cellular and molecular systems involved in RPGN.
Confrontation of kidney tissues from mouse models and human patients unravelled universal markers of pathological GEC phenotype switch: EGFR-dependent STAT3 activation and subsequent induction of miR-92a.
This latter finding led to a novel paradigm: pathological proliferation of podocytes is not only cause by mitogenic stimuli but also by miR-92a-mediated unlocking of the podocyte cell cycle through extinction of Cdkn1c, a direct miR-92a target. Therapeutic use of anti-miR-92a stopped glomerular damage in mice (Hénique et al. Nat Commun 2017 and patent).
We also found that human neutrophils synthesize endothelin-1 and have functional ETB receptors increasing adhesion to the endothelium in microfluidic flow chamber.
Intravital microscopy analyses demonstrated that blocking the ETA or the ETB receptor separately strongly influences neutrophil recruitment under inflammatory conditions in sickle cell mice.
This suggests that dual ET receptors blockade should be more effective for the treatment of sickle cell vaso-occlusive crises than selective anti-ETA strategies (Koehl, Nivoit, El Nemer & Lenoir et al., Haematologica. 2017).
Diabetic nephropathy is the leading cause of end-stage renal disease in industrialized countries. Hypertension is a common comorbidity factor of diabetes and diabetic patients with poorly controled blood pressure commonly present more severe and unclassical renal complications, highlighting the main role of hemodynamic factors to promote glomerular injury.
The integrity of the glomerular filtration barrier (GFB) is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes.
Despite the strong prevalence of diabetic nephropathy worldwide and the emergence of the recent sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, providing significant but only partial efficacy to prevent cardiovascular events and kidney failure, there are currently no therapies to specifically prevent glomerular cells injury during diabetes and hypertension.
The Lenoir’s group identified mechanisms of glomerular cell tolerance during diabetes and hypertension. Our findings have provide evidence that autophagy is a key pathway promoting tolerance of podocytes and glomerular endothelial cells, to diabetic and hypertensive stress.
We are making progress in the understanding of autophagy regulatory mechanisms in glomerular cells. We found that podocyte autophagy has an unconventional mechanism of regulation, independent to the canonical mTOR pathway (Bork et al. Autophagy 2019). We recently demonstrated that some calcium-dependent cysteine protease, calpains, regulate podocyte autophagy and inhibition of calpains minimize hypertension-induced podocyte injury via autophagy maintenance (Bensaada*, Robin* et al. Kidney International 2021).
