Abstract: SA-PO563
Increased Soluble Guanylyl Cyclase Activity in Ischemia/Reperfusion Induced AKI Suppresses PGC-1a and Mitochondrial Biogenesis
Session Information
- AKI: Other Mechanisms and Cell Cultures
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Bhargava, Pallavi, University of Arizona, Tucson, Arizona, United States
- Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States
Background
Acute Kidney Injury (AKI) can result from numerous causes such as ischemia/reperfusion (I/R) injury. We have shown that mitochondrial biogenesis (MB) is persistently suppressed following diverse injuries and that stimulation of MB, by targeting PGC-1a, the master regulator of MB, promotes recovery of renal function. Soluble guanylyl cyclase (sGC) is a heterodimer that catalyzes the production of cGMP from guanosine triphosphate (GTP). cGMP can be increased by sGC activity or by pharmacological inhibition of phosphodiesterases (PDE) 3 and 5, enzymes that degrade cGMP. Although inhibition of PDE3 and 5 induces MB and promotes renal recovery in AKI models, the role of sGC in AKI has received minimal attention.
Methods
Mice underwent bilateral I/R and were euthanized 24 h later. Kidney function was determined by serum creatinine (SCr). Cell signaling was measured using RT-qPCR and immunoblot analysis. sGC enzyme activity was determined by measuring cGMP in renal cortical homogenates.
Results
SCr increased 10-fold to 1.8 mg/dL 24 h after I/R injury. While renal cortical protein expression of the sGC subunits was not altered, sGC activity increased 1.6-fold in I/R mice compared to sham mice. Increased cGMP activated protein kinase G (PKG). In turn, phosphorylated p38, a target of PKG, increased in I/R mice. Phosphorylated FOXO1, a target of activated p38, also increased, inhibiting FOXO1 translocation into the nucleus. PGC-1a mRNA, a transcriptional target of FOXO1, decreased 24 h after I/R.
Conclusion
I/R injury initiates a signaling pathway comprised of sGC-cGMP-PKG-p38-FOXO1-PGC-1a and resulted in decreased PGC-1a transcription. These results are consistent with previous findings demonstrating decreased PGC-1a in various forms of AKI and the suppression of MB.
Funding
- Other NIH Support