Proteinuria is associated with progressive chronic kidney disease. It is well known that exposure of proximal tubular epithelial (PTEC) cells to large amounts of albumin leads to the development of tubular atrophy and fibrosis. However, the possible pathogenic role of albumin in this process has not been fully elucidated. Development of new therapeutic tools to prevent or slow the progression of proteinuric chronic kidney disease requires clear understanding of the effect of proteinuria on tubular cell function. We propose that exposure of PTEC to albumin inhibits autophagy, a critical cellular function responsible for turnover of cellular macromolecules and organelles, including dysfunctional mitochondria. Our hypothesis is that albumin impairs autophagy by one of the following mechanisms: (a) stimulating albumin receptor-mediated signaling events;(b) up-regulating mTOR, a potent autophagy inhibitor;or (c) causing lysosomal dysfunction or inhibition of autophagosomal-lysosomal fusion which, in turn, inhibits autophagy. We hypothesize that experimental inhibition of autophagy by albumin overload or by knockdown of crucial autophagic proteins will result in accumulation of dysfunctional mitochondria leading to increased production of reactive oxygen species. The resulting oxidative damage increases the permeability and depolarization of the mitochondrial membrane and facilitates the leakage of intramitochondrial components such as cytochrome c and AIF, pro-apoptotic proteins that promote cell death. In in vivo experiments, proteinuria will be correlated with autophagy, ROS production, PTEC apoptosis, tubular atrophy, fibrosis and organ function. We will use Ins2Akita/+, a diabetic mouse model that develops proteinuria, interstitial fibrosis, tubular dysfunction and atrophy. We will also test if pharmacologic up-regulation of autophagy ameliorates proteinuria-induced changes in the proximal tubule. By investigating the possible signal transduction cascades that impair autophagy, this proposal will improve our understanding of the pathogenic role of albumin in proteinuric states, an established cause of progressive chronic kidney disease, and will investigate the novel role of autophagy stimulators in ameliorating progressive organ failure. Mastering the new principles and techniques presented in this proposal is essential for my scientific development and future research productivity. They will complement my previous experiences in the lab, permit me to lay down the foundation of a unique area of research and help me make a significant contribution to the depth and breadth of research in the field of proteinuric kidney diseases. I believe that this NIH mentored award will promote my scientific maturity and allow me to transition to a level that will make me competitive for independent research support.
Proteinuria is associated with progressive chronic kidney disease which affects more that 20 million Americans. Exposure of renal proximal tubular epithelial cells to large amounts of albumin leads to the development of tubular atrophy and fibrosis which in turn results in end stage renal failure;however, the possible pathogenic role of albumin in this process is not fully elucidated. Exploring the presently unknown pathophysiologic processes in proteinuric kidney disease can lead to the development of new therapeutic tools to prevent or slow the progression to chronic kidney failure.
|Havasi, Andrea; Dong, Zheng (2016) Autophagy and Tubular Cell Death in the Kidney. Semin Nephrol 36:174-88|
|Havasi, Andrea; Lu, Weining; Cohen, Herbert T et al. (2016) Blocking Peptides & Molecular Mimicry as Treatment for Kidney Disease. Am J Physiol Renal Physiol :ajprenal.00601.2015|
|Menn-Josephy, Hanni; Lee, Carol S; Nolin, Angela et al. (2016) Renal Interstitial Fibrosis: An Imperfect Predictor of Kidney Disease Progression in Some Patient Cohorts. Am J Nephrol 44:289-299|
|Nolin, Angela C; Mulhern, Ryan M; Panchenko, Maria V et al. (2016) Proteinuria causes dysfunctional autophagy in the proximal tubule. Am J Physiol Renal Physiol :ajprenal.00125.2016|
|Havasi, Andrea; Stern, Lauren; Lo, Stephen et al. (2016) Validation of new renal staging system in AL amyloidosis treated with high dose melphalan and stem cell transplantation. Am J Hematol 91:E458-60|
|Gall, Jonathan M; Wang, Zhiyong; Bonegio, Ramon G et al. (2015) Conditional knockout of proximal tubule mitofusin 2 accelerates recovery and improves survival after renal ischemia. J Am Soc Nephrol 26:1092-102|
|Stern, Lauren; Havasi, Andrea (2015) Renal transplantation in amyloidosis and MIDD. Front Biosci (Elite Ed) 7:149-57|
|Siriwardana, Nirodhini S; Meyer, Rosana; Havasi, Andrea et al. (2014) Cell cycle-dependent chromatin shuttling of HBO1-JADE1 histone acetyl transferase (HAT) complex. Cell Cycle 13:1885-901|
|Havasi, Andrea; Haegele, Joseph A; Gall, Jonathan M et al. (2013) Histone acetyl transferase (HAT) HBO1 and JADE1 in epithelial cell regeneration. Am J Pathol 182:152-62|
|Christov, Marta; Waikar, Sushrut S; Pereira, Renata C et al. (2013) Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int 84:776-85|
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