Abstract: TH-PO1064
Aged TRPC6 KO Mice Have a Novel Renal Phenotype
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Farmer, Louise K., University of Bristol, Bristol, United Kingdom
- Gamez, Monica, University of Bristol, Bristol, United Kingdom
- Foster, Rebecca R., University of Bristol, Bristol, United Kingdom
- Saleem, Moin, University of Bristol, Bristol, United Kingdom
- Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
Background
Focal segmental glomerulosclerosis is a form of nephrotic syndrome which leads to end stage renal failure. The disease can be genetic or idiopathic and mutations in transient receptor potential cation channel 6 (TRPC6) can cause nephrotic syndrome. Patients with TRPC6 mutations tend not to develop symptoms until later life. TRPC6 KO mice have previously reported no detrimental kidney phenotype, with blood pressure, glomerular morphology and albumin excretion like WT animals. However, these have been studied early in life and to date there has been no study on the effect of TRPC6 KO with ageing. We therefore aged TRPC6 KO mice and looked at their phenotype at 10-16 months.
Methods
An ex vivo glomerular albumin permeability assay developed by our group was used to determine glomerular permeability (Desideri et al, 2018). Mouse kidneys were harvested and imaged using an electron microscope to measure the dimensions of the glomerular filtration barrier. Mouse urine was collected by spot collection and the urinary albumin-to-creatinine ratio was quantified.
Results
Aged TRPC6 KO mice were not proteinuric and had normal albumin creatinine ratios. However, we also used a highly sensitive, ex vivo glomerular permeability assay, developed by our group, to look for differences in permeability between aged TRPC6 KO and control mice. Glomerular permeability was significantly (P< 0.0001) increased in older KO mice (6.615e-007±4.002e-008 cm/s) compared to age-matched wild type controls (2.643e-007±5.332e-009 cm/s), suggesting a pathological effect of TRPC6 KO. An increased width of both ordinary (P=0.0054) and anchoring (P=0.022) podocyte foot processes was observed in the aged TRPC6 KO mice (ordinary (0.35±0.01 vs 0.27±0.01 μm) and anchoring (0.51±0.05 vs 0.29±0.03 μm)) compared to control mice (ordinary 0.27±0.01 μm) and anchoring (0.29 ± 0.03 μm)). There were also significantly fewer foot processes in the TRPC6 KO mouse P=0.046). The GBM thickness was increased (P=0.018) from 0.29±0.02 μm in control to 0.36±0.005 in KO animals, demonstrating that old TRPC6−/− mice have morphological changes on the structure of the GFB.
Conclusion
We have demonstrated that in a mouse model, knockout of TRPC6 results in increased glomerular permeability and alterations to the structure of the glomerular filtration barrier in aged mice. This phenotype correlates with disease progression in human patients.