Physiology of transport mechanisms:
- Mechanisms and regulation of endocytosis in the proximal tubule
- Salt and water handling by distal nephron segments
- Ontogeny and transcriptional regulation of transport systems
- Mechanisms of differentiation of epithelial cells
- Genome-wide association studies for renal function parameters
Pathophysiology of inherited kidney disorders:
- Mechanisms and consequences of proteinuria
- Pathophysiology of inherited forms of chronic interstitial nephritis, including uromodulin-associated kidney disorders
- Gitelman syndrome and salt-losing tubulopathies
- Clinical and genetic aspects of polycystic kidney and liver diseases
- Characterization of mouse models generated by random mutagenesis (ENU)
- Characterization of urinary biomarkers for tubular disorders
Mechanisms of water and solute transport across the peritoneal membrane:
- Improving the efficiency of water and solute removal during peritoneal dialysis
- Role and regulation of water channels in endothelial cells
- Development of mouse models of peritoneal dialysis
- Mechanisms of osmosis, characterization of alternate osmotic agents
- Genetic influence on transport parameters
Summary of research over the last five years:
Our joint work has led to the identification of mechanisms involved in rare, inherited diseases affecting the epithelial cells lining specific segments of the renal tubule. In turn, these findings provided key insights into common disorders related to kidney function. These studies provide mechanistic knowledge and new therapeutic targets to limit the clinical consequences of tubular disorders and the progression to chronic kidney disease (CKD).
Highlights of our recent work include:
* Our studies, based on cellular, mouse and human evidence, identified a new link between genetic susceptibility to salt-sensitive hypertension and CKD, and uromodulin, the most abundant protein excreted in the normal urine. We identified the biological activity of common variants in the encoding UMOD gene, the role of uromodulin in kidney damage, and showed that the ancestral, risk UMOD allele has likely been conserved through evolution because of its protective effect against urinary tract infections. These results open a new field in renal physiology and offer novel targets for the preservation of renal function and the treatment of hypertension.
* Our studies of rare inherited disorders of the proximal tubule (Dent disease, MODY3, cystinosis) demonstrated the involvement of the endolysosomal pathway in the epithelial dysfunction causing renal Fanconi syndrome. We showed that similar mechanisms sustain the epithelial dysfunction associated with specific monoclonal gammopathies. The characterization of these common pathways opens new perspectives for early interventions targeting defective lysosome-autophagy and oxydative stress.
* We discovered the role of water channels in the peritoneal membrane and identified the first agonist of AQP1, based on a bumetanide scaffold, with relevance for peritoneal dialysis and disorders of defective osmotic water transport. We extended pre-clinical studies showing an impaired vasopressin-aquaporin axis in polycystic kidney disease into the first positive RCT demonstrating the benefit of tolvaptan (antagonist of vasopressin V2 receptor) in ADPKD.