Acute kidney injury (AKI) is a growing public health burden. The syndrome itself is occurring in more diverse contexts and the long-term sequelae of AKI include chronic kidney disease (CKD). More than ever then, AKI research must identify candidate pathways that can be assessed and targeted in humans. In the first four years of this award, the applicant's laboratory has found that the mitochondrial biogenesis regulator, PGC1? (PPAR?-coactivator-1?), confers robust resistance to simple, common acute stressors that culminate in AKI such as acute systemic inflammation and renal ischemia. Moreover, we have observed that renal PGC1? expression is markedly suppressed in human AKI. Finally, we have implicated a novel downstream effector pathway for PGC1??biosynthesis of the energy carrier nicotinamide adenine dinucleotide (NAD+). Based upon these results, we hypothesize that the PGC1?-NAD+ pathway may be a critical determinant of metabolic defense against diverse renal tubular insults. To test this concept in ways that advance both our fundamental understanding of this emerging candidate and that catalyze translational efforts, we propose three parallel aims: (1) identify when in the CKD-AKI spectrum tubular PGC1? induction is most beneficial; (2) critically evaluate the role of NAD+ biosynthetic pathways in experimental AKI downstream of PGC1?; and (3) dissect the relative contributions of mitochondrial biogenesis versus NAD+ biosynthesis in the metabolic protection conferred by PGC1?. To accomplish this, our team is composed of individuals possessing complementary expertise with a proven track record of collaborating to investigate metabolism in AKI. We have developed a suite of tools ranging from metabolomics and lipidomics applications to gene-edited cells to function- ultrastructure analysis of mitochondria. The output from the proposed aims will advance our understanding of how renal tubular metabolism bridges CKD and AKI; identify specific contexts in which PGC1?-NAD+ should be pursued clinically; and deepen our fundamental understanding of PGC1? and NAD+ in renal health. In concert with a growing number of outstanding groups investigating renal metabolism, it is our hope that the proposed studies help expand this new frontier in renal biology.

Public Health Relevance

Acute kidney injury (AKI) is a common and growing public health burden. Currently, no therapy exists to prevent or accelerate recovery from AKI. This revised renewal application seeks to build on funded studies that have proposed PGC1? (PPAR?-coactivator-1?) in the renal tubule to be a promising therapeutic target. We aim to test how PGC1? and its downstream effector NAD+ modify renal health and the response of the kidney to various injuries. The results should not only open new areas of renal biology study, but critically, they should help the renal community move forward with innovative ways to assess and potentially treat this devastating syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095072-06
Application #
9613243
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-09-27
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Lynch, Matthew R; Tran, Mei T; Parikh, Samir M (2018) PGC1? in the kidney. Am J Physiol Renal Physiol 314:F1-F8
Poyan Mehr, Ali; Tran, Mei T; Ralto, Kenneth M et al. (2018) De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24:1351-1359
Drury, Erika R; Zsengeller, Zsuzsanna K; Stillman, Isaac E et al. (2018) Renal PGC1? May Be Associated with Recovery after Delayed Graft Function. Nephron 138:303-309
Poyan Mehr, Ali; Parikh, Samir M (2017) PPAR?-Coactivator-1?, Nicotinamide Adenine Dinucleotide and Renal Stress Resistance. Nephron 137:253-255
Parikh, Samir M (2017) The Angiopoietin-Tie2 Signaling Axis in Systemic Inflammation. J Am Soc Nephrol 28:1973-1982
Ralto, Kenneth M; Parikh, Samir M (2016) Mitochondria in Acute Kidney Injury. Semin Nephrol 36:8-16
Tran, Mei T; Zsengeller, Zsuzsanna K; Berg, Anders H et al. (2016) PGC1? drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531:528-32
Agarwal, Anupam; Dong, Zheng; Harris, Raymond et al. (2016) Cellular and Molecular Mechanisms of AKI. J Am Soc Nephrol 27:1288-99
Jang, Cholsoon; Oh, Sungwhan F; Wada, Shogo et al. (2016) A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22:421-6
Emma, Francesco; Montini, Giovanni; Parikh, Samir M et al. (2016) Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol 12:267-80

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