Over 26 million people in the U.S. have chronic kidney diseases, most commonly from diabetic glomerular injury. However, progression to end stage is more tightly coupled to proximal tubule disappearance (tubular atrophy), which is caused by apoptosis. In the previous funding period we determined that intracellular accumulation of a non-esterified fatty acid (NEFA) metabolite, long-chain acyl-coenzyme A (LC-CoA), stimulates tubular atrophy by a mechanism that involves inhibition of NHE1 Na+/H+ exchanger-dependent cell survival. Excess LC-CoAs are stored as cytoplasmic lipid droplets to shield cells from lipotoxicity, though this NEFA buffering capacity is limited in the proximal tubule. Multiple factors converge to cause NEFA accumulation in diabetic nephropathy, but most notably reabsorption of filtered albumin bound to NEFA. We hypothesize that luminal NEFA uptake by fatty acid transporter-2 (FATP2) causes proximal tubule lipoapoptosis, which contributes to tubular atrophy and progression of diabetic nephropathy. The hypothesis will be pursued with the following specific aims: (1) To determine whether FATP2 is the major transporter for luminal proximal tubule NEFA uptake, fluorescently labeled NEFA uptake will be measured in isolated perfused proximal tubules from FATP2-deficient mice, and apoptosis will be assayed in cultured proximal tubule cells treated with shRNAs directed against FATP2; (2) To determine the pathophysiological relevance of FATP2- mediated NEFA internalization in diabetic nephropathy 13C-labeled NEFA uptake will be assayed in vivo in eNOS-/-db/db mice prone to diabetic nephropathy, and the effects of insulin on FATP2-dependent NEFA uptake in proximal tubule cells will be measured; (3) Genetic and pharmacologic tools will be employed to test whether proximal tubule NEFA uptake regulates diabetic nephropathy progression in eNOS-/-db/db mice. Upon completion of these experiments we are hopeful that FATP2 will emerge as a druggable target for the treatment of diabetic nephropathy.

Public Health Relevance

Over 500,000 people in the U.S. have kidney failure that requires dialysis or transplantation to stay alive. The purpose of this project is to determine why kidneys fail. In particular, we plan to study biochemical pathways that prevent kidney cells from dying, which may lead to new therapies to halt the progression of kidney diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067528-09
Application #
9421553
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Ketchum, Christian J
Project Start
2005-08-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Schelling, Jeffrey R (2016) Tubular atrophy in the pathogenesis of chronic kidney disease progression. Pediatr Nephrol 31:693-706
Parker, Mark D; Myers, Evan J; Schelling, Jeffrey R (2015) Na+-H+ exchanger-1 (NHE1) regulation in kidney proximal tubule. Cell Mol Life Sci 72:2061-74
Lakhe-Reddy, Sujata; Li, Vincent; Arnold, Thomas D et al. (2014) Mesangial cell ?v?8-integrin regulates glomerular capillary integrity and repair. Am J Physiol Renal Physiol 306:F1400-9
Khan, Shenaz; Abu Jawdeh, Bassam G; Goel, Monu et al. (2014) Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. J Clin Invest 124:1057-68
Abu Jawdeh, Bassam G; Khan, Shenaz; DeschĂȘnes, Isabelle et al. (2011) Phosphoinositide binding differentially regulates NHE1 Na+/H+ exchanger-dependent proximal tubule cell survival. J Biol Chem 286:42435-45
Khan, Shenaz; Lakhe-Reddy, Sujata; McCarty, Joseph H et al. (2011) Mesangial cell integrin ?v?8 provides glomerular endothelial cell cytoprotection by sequestering TGF-? and regulating PECAM-1. Am J Pathol 178:609-20
Kim, Jane H; Konieczkowski, Martha; Mukherjee, Amitava et al. (2010) Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport. J Biol Chem 285:9995-10004
Holthouser, Kristine A; Mandal, Amritlal; Merchant, Michael L et al. (2010) Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells. Am J Physiol Renal Physiol 299:F77-90
Abu Jawdeh, Bassam G; Kanso, Abbas A; Schelling, Jeffrey R (2009) Evidence-based approach for prevention of radiocontrast-induced nephropathy. J Hosp Med 4:500-6
Schelling, Jeffrey R; Abu Jawdeh, Bassam G (2008) Regulation of cell survival by Na+/H+ exchanger-1. Am J Physiol Renal Physiol 295:F625-32

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