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Abstract: SA-PO073

Calponin-2 Dictates Kidney Fate by Regulating Ketogenesis After AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gui, Yuan, University of Connecticut School of Medicine, Farmington, Connecticut, United States
  • Zhou, Dong, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background

Energy generation is critical for tissue recovery from acute kidney injury (AKI). Amid the AKI repair process, the ketone body is a major energy source in the kidney. Our preliminary proteomic analysis indicates that the two topmost biological events after AKI are cell metabolism and actin filament binding. However, whether direct or indirect regulation exists between cell metabolism and mechanics after AKI remains unclear. To address this question, we systemically explored how Calponin 2 (CNN2), an actin filament-associated regulatory protein highlighted from our AKI proteome database, determines AKI prognosis by influencing energy consumption and generation.

Methods

AKI patients' kidney biopsy specimens were employed in this study. Two AKI animal models induced by ischemia-reperfusion injury (IRI) and cisplatin were constructed. Global-scale proteomics and in vitro / in vivo translational experiments were performed.

Results

CNN2 is induced in the diseased kidneys obtained from AKI patients and animals. It is predominantly localized in the kidney interstitial compartment. At 1 day after IRI or 3 days after cisplatin injection, knockdown of CNN2 preserved kidney functions, mitigated tubular cell death and inflammation, and promoted tubular cell proliferation. Global proteomic analysis identified that hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), a key rate-limiting enzyme of endogenous ketogenesis that promotes cell self-renewal, was significantly increased in CNN2 knockdown mice kidneys compared with controls. Accordingly, knocking down CNN2 concentrated the levels of β-hydroxybutyrate (β-OHB), the precursor of ketone bodies, and ATP production by which to release energy for AKI repair. To mimic in vivo, we silent CNN2 in cultured fibroblast and collected the conditioned medium. The conditioned medium increased the HMGCS2 level and reduced cell death in cultured tubular cells. However, these protective effects were largely abolished once knocking down HMGCS2 in tubular cells. Conversely, in vitro, exogenous CNN2 inhibited HMGCS2 expression and aggravated tubular cell death under hypoxia stress. In addition, β-OHB also exhibited a protective role in CNN2-induced tubular cell death.

Conclusion

Our results indicated that in addition to its capacity to regulate cell proliferation and motility, cell mechanics play a direct role in mediating cell metabolism to determine AKI prognosis.

Funding

  • NIDDK Support