Podocyte-Specific Overexpression of Wild Type or Mutant Trpc6 in Mice Is Sufficient to Cause Glomerular Disease

Paola Krall,Paulina Carmona-Mora,Katherina Walz,Cesar P Canales,Sergio A Mezzano,Jessica Molina,Pamela Kairath,Phillip Ruiz,J Daniel Carpio,Changli Wei,Jochen Reiser,Jing Li,Juan I Young,Christos Chatziantoniou

doi:10.1371/journal.pone.0012859

Abstract

Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6) gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS) affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2–3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated) in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease.

Highlights

Focal and Segmental Glomerulosclereosis (FSGS) is a major cause of end-stage renal disease that is increasing in frequency [1]
Mutations in the Transient receptor potential channel 6 (TRPC6) channel were found associated with FSGS in non familiar cases, one of them being of pediatric onset [30]
This paper described that all TRPC6 mutations know to date are gain of function mutations which elevate peak calcium entry or allow the TRPC6 channel to remain open for larger period of time once activated

Summary

Introduction

Focal and Segmental Glomerulosclereosis (FSGS) is a major cause of end-stage renal disease that is increasing in frequency [1]. Up to a fifth of FSGS affected patients have a high risk for progression to end-stage renal disease [2]. While the clinical presentation of FSGS is often heterogeneous, a characteristic early sign of this glomerular disease constitutes any level of proteinuria and a ‘‘focal’’ pattern of injury, meaning a few but not all of the total sampled glomeruli have ‘‘segmental’’ solidification of the tuft caused by an accumulation of extracellular matrix with obliteration of the capillary lumina (sclerosis) [2]. A working classification system which recognizes five histologic subtypes (collapsing, tip, cellular, perihilar and not otherwise specified (NOS)) can be used in the diagnosis of Primary and Secundary FSGS. Typical findings which confirm the diagnosis of FSGS include collapse, hypercellularity, perhilar hyalinosis, thickened membranes and certainly sclerosis [3]

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Conclusion