Shifts in cellular energy metabolism impact the development and progression of chronic kidney disease (CKD) through the generation of specific signals that modulate cellular differentiation and function, cell-cell interactions and inflammation. Perivascular renal interstitial cells and pericytes support the renal microvasculature and play a critical role in the pathogenesis of CKD. In kidney injury they represent major cellular sources of myofibroblasts, which promote fibrosis and the progression of CKD through the pathologic production and deposition of collagen and other extracellular matrix components in the interstitial space. Perivascular renal interstitial cells are highly sensitive to changes in tissue pO2 and respond to hypoxia with the production of erythropoietin, an oxygen-regulated erythropoiesis-stimulating glycoprotein hormone that is insufficiently produced in patients with CKD. Despite their importance in renal fibrogenesis and erythropoiesis, perivascular renal interstitial cells are poorly characterized and little is known about their metabolic functions. Here we hypothesize that shifts in energy metabolism plays a critical role in the development of renal fibrosis. Our studies aim at defining the degree of cellular and functional heterogeneity within this perivascular renal interstitial cell population and at defining the molecular mechanisms that link cellular energy and mitochondrial metabolism to fibrosis development. Specifically we a) examine oxygen-regulated metabolism in defined subsets of renal interstitial cells using temporally controlled conditional gene targeting, b) investigate the role of mitochondrial metabolism in renal microvascular homeostasis and differentiation and d) to determine to what degree metabolic reprogramming in perivascular renal interstitial cells impact the development of renal injury, inflammation and repair.

Public Health Relevance

Chronic kidney disease represents a major public health burden in the U.S. and worldwide. This grant investigates the role of oxygen, glucose and mitochondrial metabolism in renal microvascular homeostasis and chronic renal injury. Work proposed under this grant will provide novel insights into the metabolic regulation of vascular function and differentiation in chronic renal injury and kidney disease progression. A goal of this grant is to identify novel metabolic targets that can be exploited therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK081646-10A1
Application #
9522666
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2008-09-18
Project End
2022-03-31
Budget Start
2018-04-03
Budget End
2019-03-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Haase, Volker H (2017) Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies. Exp Cell Res 356:160-165
Haase, Volker H (2017) HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int 21 Suppl 1:S110-S124
Kobayashi, Hanako; Liu, Qingdu; Binns, Thomas C et al. (2016) Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin. J Clin Invest 126:1926-38
Urrutia, Andres A; Afzal, Aqeela; Nelson, Jacob et al. (2016) Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood 128:2550-2560
Bryant, Andrew J; Carrick, Ryan P; McConaha, Melinda E et al. (2016) Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 310:L249-62
Farsijani, Navid M; Liu, Qingdu; Kobayashi, Hanako et al. (2016) Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest 126:1425-37
Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy et al. (2016) Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537:234-238
Haase, Volker H (2015) A breath of fresh air for diabetic nephropathy. J Am Soc Nephrol 26:239-41
Kapitsinou, Pinelopi P; Haase, Volker H (2015) Molecular mechanisms of ischemic preconditioning in the kidney. Am J Physiol Renal Physiol 309:F821-34

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