Characterization of a Trpc6 Transgenic Mouse Associated with Early Onset FSGS
Cesar P. Canales
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Cellular and Genetic Medicine Unit, School of Medical Sciences, UNSW, Sydney, Australia.
Paola Krall
Nephrology Unit, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
Pamela Kairath
School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile.
Irene C. Perez
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA.
Miryam A. Fragoso
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA.
Paulina Carmona-Mora
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Cellular and Genetic Medicine Unit, School of Medical Sciences, UNSW, Sydney, Australia.
Phillip Ruiz
Department of Surgery and Pathology, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Division of Nephrology and Hypertension, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA.
Jochen Reiser
Department of Internal Medicine, Rush University, Chicago, USA.
Juan I. Young
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Department of Human Genetics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA.
Katherina Walz *
John P. Hussman Institute for Human Genomics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Division of Nephrology and Hypertension, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA and Department of Human Genetics, University of Miami Leonard Miller School of Medicine, Miami, Florida, USA.
*Author to whom correspondence should be addressed.
Abstract
Rationale: Mutations in Transient Receptor Potential Channel 6 (TRPC6) gene are associated with autosomal dominant focal and segmental glomerulosclerosis (FSGS). The majority of the identified mutations affect the ion channel function. Since calcium channels are promising candidate drug targets, there is an an urgent need for a mouse model to assess new therapeutic drugs and to help delineate the pathogenic process leading to FSGS. We have previously reported the generation of three independent transgenic mouse lines carrying different Trpc6 mutations that display a glomerular disease comparable to the phenotype presented by individuals with FSGS. However, the utility of these models for drug testing is dampened by the late-onset of the presentation and the mild phenotypic manifestations.
Methodology: In order to obtain a time-effective mouse model for Trpc6-associated FSGS we generated a new transgenic mutant Trpc6 mouse model emulating the amino acid change carried by the first pediatric patient of FSGS associated with a TRPC6 mutation: M132T.
Results: Mice carrying the orthologous Trpc6 M131T transgene showed early onset proteinuria and early signs of FSGS. When exploring molecular consequences of the overexpression of this mutated form of Trpc6 in podocytes, differences in expression levels of Axin2 and β-catenin were found in glomeruli from transgenic Trpc6 M131T mice. These data supports the proposed molecular mechanisms related to the activation of calcineurin-NFAT/Wnt signaling, as outcome of the increased calcium influx caused by the mutated form of Trpc6.
Conclusion: Given that the Trpc6 M131T mouse develops an early onset of FSGS-like phenotypes it represents a promising model for studying the pathogenesis of FSGS caused by TRPC6, facilitating the assessment of new drugs as treatments and allowing further studies to understand underlying molecular pathways involved in the development of the TRPC6 mediated disease.
Keywords: FSGS, TRPC6, glomerulopathies, podocytes, kidney disease, mouse models, transgenic, genetic bases of human diseases