Abstract: FR-PO934
Calcineurin Inhibitors Activate WNK1 Kinase to Preserve Glomerular and Podocyte Structure and Mechanics
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Liu, Zhenan, University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Yoon, Joonho, University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Chang, Audrey N., University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Miller, R. Tyler, University of Texas Southwestern Medical School, Dallas, Texas, United States
Background
Tacrolimus (FK-506) and cyclosporin A (CsA), both calcineurin inhibitors (CNIs), are immunosuppressants used to treat organ transplant rejection and auto-immune diseases. Although use of these drugs can be limited by side effects including hypertension, hyperkalemia, and vasculopathy with glomerulopathy, they can also protect podocytes and glomerular capillaries from injury by preserving podocyte cytoskeletal structure. Activation of WNK kinases by CNIs causes volume-dependent hypertension and hyperkalemia, but the mechanism of CNIs’ vascular and glomerular effects is not understood.
Methods
Fresh, isolated mouse glomeruli were used for measurement of WNK1 activity (measured as pOSR1), glomerular elasticity using microindentation, F/G actin ratios, and confocal imaging for glomerular structure and pOSR1. Conditionally-immortalized podocytes were used for WNK1 activity measurements (pOSR1), confocal microscopy imaging, F/G-actin ratios, pOSR1, collagen gel contraction, and migration.
Results
We found that CNIs activate WNK1 in renal glomeruli and cultured podocytes increasing pOSR1 and F-actin. Treatment of glomeruli with CNIs increases the elastic modulus (E) of glomeruli (2.4 kPa vs control 2 kPa), an effect blocked by WNK463. FK-506 increases pOSR1, F/G Actin ratios and traction by podocytes in 3-dimensional collagen gels, increases lamellipodium formation, pOSR1 localization in leading edges, and migration of cultured podocytes, effects blocked by WNK463. In glomerular capillaries, CNIs increase pOSR1, while WNK463 reduces pOSR1and disrupts capillary structure.
Conclusion
The CNI-induced increase in glomerular F-actin and E, and modifications in podocyte cytoskeletal structure, provide mechanisms by which CNIs can protect glomeruli and podocytes against injury, and illustrate a novel mechanism involving WNK1 kinase and vascular tissue. This is the first report of a function for WNK1 in glomeruli.
Funding
- NIDDK Support