Abstract: SA-PO138
The Nicotinic Acid Receptor HCA2 Regulates Progression of AKI and Development of CKD in Mouse Models of Sepsis and Postischemic Kidney Injury
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zandi-Nejad, Kambiz, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Parikh, Samir M., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Takakura, Ayumi, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background
Patients with sepsis-associated AKI (SA-AKI) have longer ICU stay compared to patients with sepsis alone, higher mortality rate and higher requirement for renal replacement therapy. SA-AKI is also a risk factor for development and progression of CKD. However, pathophysiological mechanisms of SA-AKI remain poorly understood. We have previously shown that hydrocarboxylic acid receptor 2 (HCA2) is expressed in SA-AKI kidneys and in activated macrophages and that Hca2 KO male mice have higher mortality than wild type mice in response to low-grade cecal ligation and puncture-induced sepsis (CLP-IS). We have also shown that renal tubular cell expression of the mitochondrial biogenesis factor PGC1α increases the local abundance of HCA2 ligand beta-hydroxybutyrate (β-OH B) and protects mice from experimental AKI. Thus, we hypothesized that activation of HCA2 may have a protective role in SA-AKI.
Methods
We used well-established models CLP (generate sepsis and SA-AKI), and ischemia reperfusion (IR).
Results
Here we show 100% of female Hca2 KO mice died within 3 days after severe CLP whereas 77% of WT female mice were alive at 3 days after surgery and nearly 40% of the female WT mice were alive at 2 weeks. Conversely, activation of HCA2 by nicotinic acid or β-OH B improved survival in both male and female mice after severe CLP-IS by more than 40%. Deficiency of Hca2 resulted in greater kidney interstitial fibrosis and pro-inflammatory cytokine production such as TNF-α after CLP-induced sepsis. Renal tubule specific overexpression of PGC1α (Pax8rtTA; tetO-PGC1α) improved survival and renal function during sepsis. However, deficiency of Hca2 abolished the reno-protective effects of PGC1α during SA-AKI, suggesting that HCA2 may be required for PGC1α-induced renoprotection. Finally, we further investigated the role of HCA2 on AKI-to-CKD transition. In bilateral IR (a model of AKI) and in unilateral IR (a model of CKD), Hca2-/- mice exhibited greater renal damage (assessed by pathology and BUN) and increased pro-inflammatory cytokine production compared with wild-type mice.
Conclusion
Considered together, we propose that a positive feedback loop of HCA2 activation through PGC1α signaling may thwart maladaptive repair, thereby delaying or inhibiting transition from AKI to CKD.
Funding
- Private Foundation Support