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

• Published in: Scientific reports 2020-02, Vol.10 (1), p.2056, Article 2056
• Main Authors: Córdoba-David, Gina, Duro-Castano, Aroa, Castelo-Branco, Regiane Cardoso, González-Guerrero, Cristian, Cannata, Pablo, Sanz, Ana B, Vicent, María J., Ortiz, Alberto, Ramos, Adrián M.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/2; 13/21; 13/51; 13/95; 14/19; 38/77; 631/154; 64/60; 692/4022/1585/4; 96/31; Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - immunology; Acute Kidney Injury - pathology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Biological properties; Caspase; Cell death; Cell Line; Diarylheptanoids - chemistry; Diarylheptanoids - pharmacology; Diarylheptanoids - therapeutic use; Disease Models, Animal; Drug Evaluation, Preclinical; Drug therapy; Female; Ferroptosis; Folic acid; Folic Acid - toxicity; Glucuronidase - metabolism; Humanities and Social Sciences; Humans; Kidney Tubules - drug effects; Kidney Tubules - pathology; Kidneys; Klotho protein; Klotho Proteins; Mice; Molecular Conformation; multidisciplinary; Necroptosis; Necrosis - drug therapy; Necrosis - immunology; Necrosis - pathology; NF-kappa B - metabolism; NF-κB protein; Polyglutamic Acid - chemistry; Polyglutamic Acid - pharmacology; Polyglutamic Acid - therapeutic use; Polyphenols; Protective Agents - chemistry; Protective Agents - pharmacology; Protective Agents - therapeutic use; Public health; Renal function; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - immunology; Structure-Activity Relationship; Transcription activation; Transcription, Genetic - drug effects; Tumor necrosis factor-α; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-58974-9

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.