Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate

Gina Córdoba-David,Pablo Cannata,Alberto Ortiz,Regiane Cardoso Castelo-Branco,Cristian González-Guerrero,María J Vicent,Ana B Sanz,Adrián M Ramos,Aroa Duro-Castano

doi:10.1038/s41598-020-58974-9

Abstract

The lack of effective pharmacological treatments for acute kidney injury (AKI) remains a significant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (St-PGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and inflammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGA-based therapeutics may improve nephroprotective properties of current AKI treatments.

Highlights

Acute kidney injury (AKI) involves a sudden and generally transient loss of glomerular filtration leading to the retention of damaging nitrogenous byproducts normally excreted in the urine
We explored whether St-PGA-CL-BDMC may inhibit necroptosis, a main type of regulated necrosis actively involved in acute kidney injury (AKI)
As St-PGA-CL-BDMC prevented critical processes involved in AKI pathogenesis in cultured tubular cells, we explored the nephroprotective potential of our novel conjugate in vivo in mice with folic acid (FA)-AKI

Summary

Introduction

Acute kidney injury (AKI) involves a sudden and generally transient loss of glomerular filtration leading to the retention of damaging nitrogenous byproducts normally excreted in the urine. The inhibition of overall caspase activity failed to improve nephrotoxic AKI6 In this regard, caspase activation is involved in cellular events beyond cell death regulation, including, among others, cell cycle and the regulation of proliferation[7,8]. BDMC prevents kidney fibrosis by activating fibroblast apoptosis[14] Despite their efficacy and safety profile, the extremely low bioavailability of curcuminoids, resulting from a combination of poor solubility and low stability, limits their therapeutic application[15]. PGA homopolymers, star-shaped PGAs, and crosslinked-star-shaped PGAs purified through covalent capture of self-assembled nanostructures modulate cellular uptake and PK23,24 These carriers present a high control on the polymerization process as well as the possibility of post-polymerization with drugs as well as targeting residues[25], increasing, if needed, the potential of directed molecule design to improve their renal targeting capacity. We discovered the superior nature of St-PGA-CL-BDMC when compared to the “free” form of BDMC with regards to protection in cultured cells treated with lethal proinflammatory stimuli and experimental murine nephrotoxic AKI models

Methods

Results

Conclusion