Theme 2 : Mechanisms of acute kidney injury and repair

Team leaders : C Chadjichristos (CR), C Chatziantoniou (DR), J Hadchouel (DR), D Dreyfuss (PU-PH), JC Dussaule (PU-PH), S Gaudry (PU-PH), A Hertig (PU-PH), E Rondeau (PU-PH), D Buob (MCU-PH), P Galichon (MCU-PH), YC Dubois-Xu (AT-AS)
Team contributors : L Abbad (Post-Doc), C Mousseaux (PhD)

In recent years, important experimental and epidemiological evidence has accumulated showing a link between AKI and CKD. Indeed, experimental models of AKI have shown that some of the acute kidney lesions observed in AKI evolve toward chronic renal abnormalities notably tubular atrophy, reduced tubular capillary density and interstitial fibrosis. The epidemiological association between the occurrence of AKI and CKD has been demonstrated in multiple clinical series. Thus, a 9-fold increase in the occurrence of CKD and a 3-fold increase in that of End Stage Renal Disease have been shown recently in AKI patients, and the risk of CKD was correlated with the severity of the acute episode. Inversely, AKI can occur mainly in patients who already have chronic but undetectable kidney damage, thus creating a two-way interaction between AKI and CKD.

For these reasons, one of the themes of our project will aim at deciphering the mechanisms promoting AKI and at defining how an efficient repair can be achieved. Our driving hypothesis is that the interaction between the renal microcirculation and tubular epithelial cells is a primary target of the aggressions leading to AKI and that the cell adaptation to the postaggression environment induces phenotypic alterations and a fibrogenic process promoting interstitial fibrosis and tubular atrophy. The applied strategy consists in studying the short or long-term outcome of renal function or structure after ischemia/reperfusion (I/R) in transgenic models in which the deletion and/or overexpression of candidate genes is conditionally controlled (time and tissue conditional). We will build on our experience with the CKD mediators we have already identified, and we will start by investigating the most promising of them (Cx43, Notch3, Periostin). We have obtained preliminary evidence showing that these genes are involved in AKI. In addition, we will test some new players (WNK1, miR-21, Nupr1), for which we recently obtained preliminary data. A particular focus will be given to the identification and discrimination between mediators promoting a « real » repair (in which the damaged cells are replaced by an identical, normal cell) vs « apparent » repair (in which the replacing cells look normal, but trigger an inflammatory or fibrotic process).