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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095072-02
Application #
8554360
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-09-27
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$365,205
Indirect Cost
$155,317
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Xie, Zhihui; Ghosh, Chandra C; Parikh, Samir M et al. (2014) Mechanistic classification of the systemic capillary leak syndrome: Clarkson disease. Am J Respir Crit Care Med 189:1145-7
Stiehl, Thomas; Thamm, Kristina; Kaufmann, Jörg et al. (2014) Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis. Crit Care Med 42:e654-62
Tran, Mei; Parikh, Samir M (2014) Mitochondrial biogenesis in the acutely injured kidney. Nephron Clin Pract 127:42-5
Maski, Manish R; Parikh, Samir M (2014) The vasculature in diabetic nephropathy: all tied up? J Am Soc Nephrol 25:1-3
Parikh, Samir M (2013) Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury. Curr Opin Crit Care 19:554-9
Parikh, Samir M (2013) Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence 4:517-24
Karumanchi, S Ananth; Parikh, Samir M (2013) Moving forward in sepsis research. Am J Respir Crit Care Med 188:1264-5