Kidney Week

Abstract: SA-PO096

Inhibition of PTP1b via Milk Exosome-Mediated Small Interfering RNA (siRNA) Delivery Is a Novel Therapeutic Approach for AKI

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Kim, Myung-Gyu, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Myung-Gyu Kim, MD

• Jang, Yookyung, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Yookyung Jang, MD

• Choi, Young Eun, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Young Eun Choi, MD

• Yoon Sook, Ko, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Ko Yoon Sook, MA

• Hee Young, Lee, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Lee Hee Young, MA

• Oh, Sewon, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Sewon Oh, MD, PhD

• Jo, Sang-Kyung, Korea University Anam Hospital, Seoul, Korea (the Republic of)

Sang-Kyung Jo, MD, PhD

Background

Protein tyrosine phosphatase-1B (PTP1b) plays a crucial role in regulating insulin, leptin sensitivity, and inflammatory responses, rendering it a promising therapeutic target for diseases like diabetes, obesity, and neuroinflammation. Despite its well-established significance in various conditions, its involvement in kidney disease remains largely unexplored.

Methods

In this study, we developed an innovative siRNA delivery system using exosomes derived from milk to encapsulate PTP1b siRNA (PTP1b siR@mExo), with the aim of investigating its impact on acute kidney injury (AKI). C57BL/6 mice were subjected to bilateral ischemia reperfusion injury (IRI), and PTP1b siR@mExo was pretreated at -6, -4, and -2 hrs.

Results

In vitro studies demonstrated better cellular uptake of Cy3-labeled PTP1b siR@mExo by human proximal tubule cells (HK2) with superior stability compared to treatment with PTP1b siRNA alone. Moreover, in mice, PTP1b siR@mExo exhibited highly efficient kidney delivery, reaching maximum absorption at 2 hours, sustaining elevated levels up to 48 hours, followed by accumulation in the liver and spleen, indicating milk exosomes as a novel siRNA delivery system. PTP1b expression was notably observed on tubules and glomeruli, and pre-treatment with PTP1b siR@mExo in IRI effectively reduced PTP1b levels in the kidney. This reduction was accompanied by decreased expression of inflammatory cytokines (TNF-α, IL-6, IL-1β), alleviated endoplasmic reticulum stress (CHOP), diminished DMAP signal (HMGB1), and a significant improvement in renal function.

Conclusion

In conclusion, our study demonstrated that milk-derived exosomes, with superior structural stability, serve as efficient carriers for siRNA, and showed the efficacy of milk-derived exosomes carrying PTP1b siRNA in treating IRI. The inhibition of PTP1b emerges a promising novel therapeutic target for AKI, providing valuable avenues for further exploration and intervention strategies in kidney disease.

Funding

• Government Support – Non-U.S.