Acute kidney injury (AKI) is a major complication for hospitalized patients, and renal ischemia is a predominant risk factor. Intensive research into mechanisms underlying renal dysfunction following ischemia have not translated to new therapies, in part because different forms of ischemia may involve non- overlapping molecular pathways. RATIONALE: PGC-1a, a regulator of mitochondrial biogenesis, is heavily expressed in the proximal tubule, becomes suppressed early during sepsis and ischemia-reperfusion injury, and in both situations, exacerbates renal function when genetically deleted from the proximal tubule. Human proximal tubular cells respond to inflammatory mediators by suppressing downstream effectors of PGC-1a and diminishing oxygen consumption, changes reversed by forced expression of PGC-1a. HYPOTHESIS: This proposal will test the hypothesis that suppression of PGC-1a may be a shared mechanism that exacerbates renal function in two forms of ischemic AKI, sepsis and ischemia-reperfusion injury (IRI).
AIMS :
The first aim will investigate mechanisms that enable inflammatory mediators to suppress PGC-1a expression in primary human proximal tubular cells.
The second aim will use models of sepsis and IRI in proximal tubular PGC-1a knockout mice to elucidate critical downstream effectors of PGC-1a that may be unique or shared in these two forms of AKI.
The third aim will ask whether proximal tubular induction of PGC- 1a can ameliorate these forms of AKI by applying pharmaceutical inducers in wildtype, global and tubule- specific knockout mice. RESEARCH DESIGN: The design offers loss- and gain-of-function experiments to examine upstream regulators and downstream effectors of PGC-1a. The experimental design will integrate findings across cellular and live animal experiments, imaging modalities and biochemical studies, using stringent genetic tools to address the core hypothesis.
Sepsis and ischemia-reperfusion injury are major contributors to ischemic renal injury suffered by hospitalized patients. The effect of PGC-1a in experimental models of both suggests that this molecule may participate in a general mechanism of ischemic renal injury. Understanding how PGC- 1a becomes suppressed in these settings and what effectors of PGC-1a are most critical has potential not only to advance our fundamental understanding of renal biology, but also to translate into novel therapeutic possibilities for this common and morbid disease.
Acute kidney Injury (AKI) is a costly and morbid complication that affects 2-7% of all hospitalized patients. No effective therapies exist to combat this problem We have found that mitochondria-the energy-producing factories of the cell-within the kidney become injured as AKI develops and that a unique molecular pathway governed by a gene called PGC-1alpha helps the kidney rebuild its mitochondria as it attempts to recover from AKI. In this application, we will ask whether this new insight has potential to translate into a first-i-class therapy for people afflicted by this disorder.
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 22 publications
