Kidney Week

Abstract: FR-PO173

The 5-HT1F Receptor as an In Vivo Regulator of Renal Mitochondrial Homeostasis

Session Information

• Mitochondriacs and More
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 002 AKI: Repair and Regeneration

Authors

• Gibbs, Whitney Sharee, Medical University of South Carolina, Charleston, South Carolina, United States

Whitney Sharee Gibbs,

• Collier, Justin B., Medical University of South Carolina, Charleston, South Carolina, United States

Justin B. Collier,

• Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States

Rick G. Schnellmann,

Background

Mitochondrial dysfunction limits repair mechanisms and restoration pathways required for the recovery of cellular functions following acute kidney injury. Stimulation of the 5-hydroxytryptamine 1F (5-HT_1F) receptor induces new, functional mitochondria through mitochondrial biogenesis (MB), resulting in accelerated renal recovery following ischemia/reperfusion (IR) induced acute kidney injury in mice. The goal of this study was to determine the contribution of the 5-HT_1F receptor in the regulation of renal mitochondrial homeostasis and renal function in healthy and injured mice.

Methods

Male 5-HT_1F receptor knockout (KO) mice and age-matched controls (WT) were euthanized at 10 and 26 weeks of age. In a second experiment, 10 week old male 5-HT_1F receptor WT and KO mice underwent renal IR injury and were euthanized at 24 hr. Renal mitochondrial homeostasis was assessed by RT- qPCR. Kidney function were assessed using serum creatinine and renal cortical KIM-1 and NGAL.

Results

In 5-HT_1F receptor KO mice, components of the electron transport chain, including ATP synthase β (ATSβ) and COX1 mRNA were elevated 1.3- and 1.6-fold at 10 weeks of age and these increases corresponded with elevated mitochondrial DNA (mtDNA) copy number. At 26 weeks of age, the master regulator of MB, peroxisome proliferator- activated receptor g coactivator- 1α, PGC-1α, ATPSβ, and mtDNA copy number were elevated 1.7-, 1.8- and 1.7-fold compared to WT mice. In addition, the mitochondrial fission protein Drp1 increased 1.7-fold at 10 weeks of age and remained elevated at 26 weeks of age in KO mice.

The 5-HT_1F receptor KO mice did not exhibit basal renal injury. At 24 hr following renal IR, KO mice exhibited greater renal cortical levels KIM-1 and NGAL than WT mice. Serum creatinine was greater in KO mice compared to WT mice after IR. Finally, PGC-1α was decreased in IR KO mice but not in WT mice.

Conclusion

These findings reveal that mitochondrial homeostasis is disrupted in 5-HT_1F receptor KO mice, resulting in compensatory MB and mitochondrial fission. Moreover, the absence of the 5-HT_1F receptor potentiates tubular injury and suppresses MB in IR injury mice. These results demonstrate the 5-HT_1F receptor is a key mediator of MB and renal injury

Funding

• NIDDK Support