Renal subcapsular delivery of PGE2 promotes kidney repair by activating endogenous Sox9+ stem cells

Shang Chen,Haoyan Huang,Yue Liu,Chen Wang,Xiaoniao Chen,Yuqiao Chang,Yuhao Li,Zhikun Guo,Zhibo Han,Zhong-Chao Han,Qiang Zhao,Xiang-Mei Chen,Zongjin Li

doi:10.1016/j.isci.2021.103243

Abstract

SummaryProstaglandin E2 (PGE2) has recently been recognized to play a role in immune regulation and tissue regeneration. However, the short half-life of PGE2 limits its clinical application. Improving the delivery of PGE2 specifically to the target organ with a prolonged release method is highly desirable. Taking advantage of the adequate space and proximity of the renal parenchyma, renal subcapsular delivery allows minimally invasive and effective delivery to the entire kidney. Here, we report that by covalently cross-linking it to a collagen matrix, PGE2 exhibits an adequate long-term presence in the kidney with extensive intraparenchymal penetration through renal subcapsular delivery and significantly improves kidney function. Sox9 cell lineage tracing with intravital microscopy revealed that PGE2 could activate the endogenous renal progenitor Sox9+ cells through the Yap signaling pathway. Our results highlight the prospects of utilizing renal subcapsular-based drug delivery and facilitate new applications of PGE2-releasing matrices for regenerative therapy.

Highlights

Acute kidney injury (AKI), which leads to abrupt loss of kidney function, is highly associated with the subsequent risks of chronic kidney disease and end-stage renal disease, which will lead to the need for lifelong dialysis and renal replacement therapy and cause high morbidity and mortality (James et al, 2020; Liu et al, 2020; Zhang et al, 2020; Zhang and Li, 2020)
To improve the therapeutic efficacy of Prostaglandin E2 (PGE2), we developed a PGE2 release matrix by cross-linking collagen type I with 4-hydrazinobenzoic acid (HBA)-polyethyleneimine (PEI), which was achieved by the reaction of the amine group on HBA with the carbonyl group on PGE2 through condensation reactions (Figures 1A and S1A–S1C)
The carbonyl ($1,726 cmÀ1) vibrations of PGE2 disappeared in the spectra of PEI-HBA-PGE2, demonstrating that hydrazone bonds were formed and that no free PGE2 existed in addition to PEI-HBA-PGE2 (Figure 1B)

Summary

Introduction

Acute kidney injury (AKI), which leads to abrupt loss of kidney function, is highly associated with the subsequent risks of chronic kidney disease and end-stage renal disease, which will lead to the need for lifelong dialysis and renal replacement therapy and cause high morbidity and mortality (James et al, 2020; Liu et al, 2020; Zhang et al, 2020; Zhang and Li, 2020). Local delivery results in high drug deposition and even toxic concentrations but leads to a dose that is lower than that required in more distant areas of the injected tissue. Intrarenal artery injection or systemic administration will lead to poor local retention and insufficient distribution throughout the entire renal parenchyma over time (Segura-Ibarra et al, 2017). Renal subcapsular spaces under kidney capsules located on the surface of the kidneys have been widely used for cell or tissue transplantation because cells exhibit better growth in these spaces (Cunha and Baskin, 2016; van den Berg et al, 2018), and this provides insight into the use of subcapsular transplantation for AKI therapy to increase drug concentrations in the whole kidney (Dankers et al, 2015; Morizane and Bonventre, 2017; Segura-Ibarra et al, 2017)

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