Genetic dissection of the SEMA3C/Neuropilin 1 signalling pathway in Chronic Kidney Disease progression

Informations projet

SEMA3C

N° de convention de subvention: 704450

DOI

10.3030/704450

Projet clôturé

Date de signature de la CE 18 Mars 2016

Date de début 5 Septembre 2016

Date de fin 4 Septembre 2018

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 185 076,00

Contribution de l’UE

€ 185 076,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - SEMA3C (Genetic dissection of the SEMA3C/Neuropilin 1 signalling pathway in Chronic Kidney Disease progression)

Période du rapport: 2016-09-05 au 2018-09-04

Résumé du contexte et des objectifs généraux du projet

Regardless of the initial insult, human Chronic Kidney Disease (CKD) is characterised by progressive destruction of the renal parenchyma and the loss of functional nephrons, the filtering units of a kidney. The worldwide incidence of CKD has reached epidemic proportions and is a major health care burden, with an estimated 10-14% of the adult population known to have CKD. Diabetes and hypertension are major contributors to the global burden of the disease and are important CKD risk factors. Inexorable progression to kidney failure is predicted for many CKD patients with high risk of becoming dependent on renal replacement therapies (hemodialysis or transplantation). The financial impact of CKD is large, with particularly high costs relating to renal replacement therapies. For instance, the annual cost of CKD to the French Securite Sociale is estimated at €3.5 billion. The only option for reducing the dialysis population or for keeping it stable over the long term is to improve the early detection of CKDs.

The diagnosis currently depends on rather late markers of kidney injury such as albuminuria or on decreased kidney functions (i.e. abnormal glomerular filtration rate). A key challenge for medical planning is to better understand the mechanisms of CKD progression in order to target pharmaceutical interventions at the early stages of the disease. This area of research is receiving increasing attention as the discovery of novel therapeutic targets/predictive biomarkers of renal fibrosis will facilitate the development of preventive therapies.

Our research has established a novel pathway as a valid drug target in this area. The rationale for this contention is based on our data implicating the protein SEMA3C and its receptor NRP1 as having a fundamental role in CKD progression. Our project investigated the disease biology of CKD and provided an improved mechanistic understanding of the disease. Our work established a hierarchy towards using the semaphorin-neuropilin signalling pathway as novel therapeutic targets in kidney disease and opened up new directions for the development of novel treatments targeting this disease spectrum. Furthermore, our project has the potential to provide a new biomarker that will be used to set up rapid, reliable and non-invasive tests for monitoring and prediction of CKD.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The MSC fellowship allowed me to earn new competence and technical skills in all the research methodology I propose to follow in the future.
Throughout the course of my project, I learnt and performed the following work tasks:
- Induce kidney fibrosis systematically, whether by surgical or chemical methodologies.
- Assay fibrosis status in a given specimen by all the relevant techniques.
- Assay kidney injury at the functional and morphological levels.
- Collect blood and urinary samples and assay kidney function by biochemical analysis.
- Measure vascular permeability in vivo using two different techniques.
- Analyse of human materials, biopsies and urinary samples.
This acquired knowledge is critical in term of carrier progression because it represents the technical foundations of any projects I plan to develop in the future.

I found that SEMA3C was not only an early marker of renal damage in both humans and mice but also an active player in disease progression. Using conditional mutagenesis, I showed that a down-regulation of Sema3C does improve renal induced-fibrosis following renal injury, central to the proposed hypothesis of a causative role for Sema3C-driven pathways in kidney disease. Second, we have obtained convincing data that SEMA3C is indeed detectable in the urine of renal disease patients and can potentially serve as a predictive biomarker for CKD progression.

I participated in the following dissemination and outreach activities:
September 2018: Group Cohesion/Team Building event for INSERM UMRS 1155 research centre, Lyons-la-Forêt, France.
April 2018: ERCSG (European Renal Cell Study Group), Florence, Italy.
May 2017: Promote Marie Curie actions (H2020), French Minister for Education and Research, Paris, France.
April 2017: ERCSG (European Renal Cell Study Group), Gottingen, Germany.

Finally I had the opportunity to participate in training and education activities which are also a way to disseminate knowledge within the scientific community, notably to junior members. I trained the following students:
-Guanyu YE, M2, Paris Diderot Medicine faculty, Paris, France 22.01.2018 – 23.07.2018
-Christie Mitri, M1, Sorbonne Université, Paris, France 01.03.2018 – 01.05.2018
-Camille Monier Vinard, Internship, Saint Louis de Gonzague College, Paris, France, 19-30.06.2017.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

I think our target offers better perspectives and therapeutic options to cure kidney disease because:
1. Our target SEMA3C modulates peritubular microvasculature functions and prevents oxygen and nutrients supply to the injured kidney. In a therapeutic point of view, it is highly relevant to maintain a healthy renal microvasculature, which would facilitate the wound healing response; tubular restauration and prevent the kidney to progress to chronic inflammation, fibrosis and capillary rarefaction. In that sense, we think that by acting on our target, one can preserve the vital function of the kidney microvasculature which role is to keep renal cell alive.
2. NRP1 is expressed in the cells which proliferate and transdifferentiate to give rise to the most pathological implicated-cells of the disease: the myofibroblasts. In a therapeutic point of view, it is highly relevant to block the processes leading to myofibroblast differentiation from a defined progenitor cell population rather than trying to block pathological matrix deposition from an already differentiated myofibroblast cell population.

We believe our research has vast translational potentials, which can benefit the European economy and public health.
Because the kidney benefits from rapid, vast blood flow physically and subsequent glomerular filtration and tubular absorption, it is an excellent target organ for any small-molecule inhibitors given intravenously. For instance, fluorescently labelled siRNAs accumulate 40 times more in the kidney than in any other organs. In that respect, I also contacted GSK for potential collaborative work in relation to the test of intravenous doses of small-molecule inhibitors to blunt CKD progression in the mouse. My project was selected and I will soon be presenting my research to validate (or not) our potential collaboration. I also engaged in partnership with the BAYER and was awarded a Grants-4-targets focus grant to carry on investigating the role of SEMA3C/NRP1 in CKD progression.
Because we validated that SEMA3C was detectable in the urine of adult and paediatric patients, we now would like to determine whether there is a correlation between the urinary levels of SEMA3C and CKD progression. Through a novel national collaboration with the laboratory of Pr. Fabiola Terzi, Necker Institute, Paris, France, we will screen a NephroTest adult cohort composed of 250 patients with CKD disease, approved and sponsored by INSERM. This future study could potentially provide a new biomarker that will be used to set up rapid, reliable and non-invasive tests for monitoring and prediction of CKD. This should improve diagnostic and facilitate prognostic counselling.

schematic-marie-curie-2018.jpg