New Approaches to the Treatment of Dense Deposit DiseaseJournal of the American Society of Nephrology : JASN - Tập 18 Số 9 - Trang 2447-2456 - 2007
Richard J. Smith, Jessy J. Alexander, Paul N. Barlow, Marina Botto, Thomas L. Cassavant, H. Terence Cook, Santiago Rodrı́guez de Córdoba, Gregory S. Hageman, T. Sakari Jokiranta, William J. Kimberling, John D. Lambris, Lynne D. Lanning, Vicki Levidiotis, Christoph Licht, Hans Lutz, Seppo Meri, Matthew C. Pickering, Richard J. Quigg, Angelique L. Rops, David J. Salant, Sanjeev Sethi, Joshua M. Thurman, Hope F. Tully, Sean P. Tully, Johan van der Vlag, Patrick D. Walker, Reinhard WuCombining Diaeresisrzner, Peter F. Zipfel
The Calcium-Dependent Protease Calpain-1 Links TRPC6 Activity to Podocyte InjuryJournal of the American Society of Nephrology : JASN - Tập 29 Số 8 - Trang 2099-2109 - 2018
Kim A.T. Verheijden, Ramon Sonneveld, Marinka Bakker-van Bebber, Jack F.M. Wetzels, Johan van der Vlag, Tom Nijenhuis
Background
The hallmark of podocytopathies, such as FSGS, is podocyte injury resulting in proteinuria. Transient receptor potential channel C6 (TRPC6) is a calcium-conducting ion channel expressed at the slit diaphragm. TRPC6 gain-of-function mutations and glomerular TRPC6 overexpression are associated with proteinuria. However, the pathways linking TRPC6 to podocyte injury, which is characterized by loss of the slit diaphragm protein nephrin, activation of several intracellular pathways (including calcineurin-NFAT signaling), and cytoskeletal rearrangement, remain elusive.
Methods
We tested whether the calcium-dependent protease calpain-1 mediates TRPC6-dependent podocyte injury in human and experimental FSGS and cultured podocytes.
Results
Compared with kidneys of healthy controls, kidneys of patients with FSGS had increased TRPC6 expression, increased calpain and calcineurin activity, and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability. In a rat model of human FSGS, increased glomerular and urinary calpain activity associated with reduced Talin-1 abundance, enhanced calcineurin activity, and increased proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects. In cultured podocytes, pharmacologic stimulation of TRPC6-dependent calcium influx increased calpain-1 and calcineurin activity and reduced Talin-1 expression, and knockdown of TRPC6 or calpain-1 prevented these effects.
Conclusions
We elucidated a novel mechanism that links TRPC6 activity to calpain-1 activation and through Talin-1 loss and possibly, calcineurin activation, the podocyte injury characterizing FSGS. Therefore, calpain-1 and/or TRPC6 inhibition could be future therapeutic options to treat patients with FSGS or other podocytopathies.
Cellular Regulation by Hydrogen PeroxideJournal of the American Society of Nephrology : JASN - Tập 14 Số suppl_3 - Trang S211-S215 - 2003
Sue Goo Rhee, Tong-Shin Chang, Yun Soo Bae, Seung-Rock Lee, Sang Won Kang
Dynamin–Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic NephropathyJournal of the American Society of Nephrology : JASN - Tập 27 Số 9 - Trang 2733-2747 - 2016
Bernard Ayanga, Shawn S. Badal, Yin Wang, Daniel L. Galvan, Benny Hung‐Junn Chang, Paul T. Schumacker, Farhad R. Danesh
Mitochondrial fission has been linked to the pathogenesis of diabetic nephropathy (DN). However, how mitochondrial fission affects progression of DN in vivo is unknown. Here, we report the effect of conditional podocyte–specific deletion of dynamin-related protein 1 (Drp1), an essential component of mitochondrial fission, on the pathogenesis and progression of DN. Inducible podocyte–specific deletion of Drp1 in diabetic mice decreased albuminuria and improved mesangial matrix expansion and podocyte morphology. Ultrastructure analysis revealed a significant increase in fragmented mitochondria in the podocytes of wild–type diabetic mice but a marked improvement in mitochondrial structure in Drp1-null podocytes of diabetic mice. When isolated from diabetic mice and cultured in high glucose, Drp1-null podocytes had more elongated mitochondria and better mitochondrial fitness associated with enhanced oxygen consumption and ATP production than wild-type podocytes. Furthermore, administration of a pharmacologic inhibitor of Drp1, Mdivi1, significantly blunted mitochondrial fission and rescued key pathologic features of DN in mice. Taken together, these results provide novel correlations between mitochondrial morphology and the progression of DN and point to Drp1 as a potential therapeutic target in DN.
