A novel druggable pathway of chronic kidney disease – STOP-CKD

Chronic kidney disease (CKD), a major socioeconomic worldwide public health burden, is characterized by a progressive decline in renal function to end stage renal disease that can occur irrespective of the cause of the renal damage once a critical number of nephrons has been lost. Understanding the physiopathology of CKD progression is therefore a prerequisite for the development of efficient preventive strategies.

The signaling pathways involved in CKD progression are still poorly understood. Among the possible candidates, the EGFR (Epidermal Growth Factor Receptor) pathway may play a role. However, despite its pharmacological inhibition has been shown to slow down CKD progression in preclinical studies, its extension to human is not straightforward because of adverse side effects. To circumvent this problem, over the last years, we have focused our efforts on the identification of the critical mediators of EGFR pathway that may be more safety druggable. Our recent results indicated that the nature of the ligand, in particular EGF and TGF-?, determines the fate of remnant kidneys towards compensation or deterioration. Interestingly, we have identified a kinase (kinase 1), selectively recruited by EGFR upon TGF-? stimulation, that we showed mediating the deleterious effect of TGF-?, by favoring the cleavage and the nuclear translocation of the intracellular domain of CD44. More importantly, a pilot study indicated that the use of a kinase 1 inhibitor prevents lesion development after subtotal nephrectomy.

We thus hypothesized that inhibiting this pathway should prevent the development of renal lesions during CKD, circumventing the adverse effects of EGFR inhibition.

Very little is known about the molecular pathways that act downstream kinase 1. The objectives of our project are:

1) characterize the signaling pathways and the genetic networks that mediate the deleterious effect of kinase 1 during CKD progression. We will identify the phospho-targets of Kinase 1, as well as its partners. In parallel, through RNAseq and CHIPseq experiments, we will identify the genetic networks triggered by kinase 1.

2) investigate the ability of the kinase 1 inhibitor to attenuate the renal deterioration process in three pre-clinical CKD mouse models : (i) the subtotal nephrectomy model (excision of 75 % of total renal mass); (ii) the diabetic nephropathy model (BTBR ob/ob transgenic mice), and (iii) the Alport disease model (Col4a3 transgenic mice). The impact on renal function (transdermal measured GFR) and renal morphology will be investigated.

3) extend our experimental finding to humans by investigating kinase 1 pathway activation in human CKD samples. Renal biopsies from CKD patient with different etiologies will be studied. In parallel, we will determine if the urinary excretion of CD44, a downstream target of kinase 1, can predict CKD progression.

This research project is based on a multidisciplinary approach that involves cell biology, transcriptomics, proteomics and pharmacological studies to improve our knowledge of the complex pathogeneses of CKD progression. The results of this research proposal should provide a novel therapeutic option, namely Kinase 1 inhibition, able to slow down CKD progression and thus to improve the care of CKD patients.