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

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 PGAbased therapeutics may improve nephroprotective properties of current AKI treatments. 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. Independently of its etiology, AKI usually implies extensive renal parenchymal injury, which, in the case of unsuccessful repair, favors the progression of AKI to chronic kidney disease (CKD). The mortality of AKI may be as high as 50%, and currently, there exist no specific therapies to attenuate AKI or accelerate recovery beyond dialysis 1. Thus, there is an unmet clinical need for novel AKI treatments. During the initial stages of AKI, proximal renal tubular cell death triggers a cascade of damaging events, including inflammation, that amplifies kidney injury 2,3. Thus, the control and execution of apoptosis and several kinds of regulated necrosis depend on environmental conditions as well as on the recruitment of intracellular cell death pathways. Distinct forms of cell death are amenable to pharmacological modulation. Strategies to specifically inhibit caspases, the final executioners of apoptosis, decrease apoptosis, inflammation, and improve renal function in experimental ischemia/reperfusion or septic AKI 4,5. However, the inhibition of overall caspase activity failed to improve nephrotoxic AKI 6. 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. Strategies that interfere with initial or intermediate regulators of caspase activity, like protein kinases, survival factors, cytokine death receptors, oxidative stress factors, apoptosome factors, and tumor-suppresso...

Recent advances in nanotherapeutics for the treatment and prevention of acute kidney injury

“…However, due to the low water solubility and permeability, flavonoids are extremely limited in the treatment of AKI. Nanocarriers can improve the availability and efficacy of flavonoids [73] . Zhang and colleagues prepared water-soluble eupafolin NPs using polyvinyl alcohol (PVA) and Eudragit E100, which can resolve the physicochemical drawbacks of the original eupafolin, and improve the water solubility by reducing the particle size, with no toxicity to normal renal cells.…”

“…Due to the strict selectivity of the kidney, only limited nanomaterials and macromolecular are used for kidney-targeted drug delivery, such as poly (vinyl pyrrolidone dimethyl maleic acid copolymer (PVD), polyglutamate, low molecular weight chitosan (LMWC), low molecular weight proteins (LMWP), liposomes, biopolymers, NPs, prodrugs and specific antibodies [30 , 73 , 80 , 81] . The applications of kidney-targeted drug delivery system for AKI therapy will be discussed in detail from two aspects: passive or active targeting in the following section.…”

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

“…1) and ANG via a bioresponsive disulfide linker (St-Cl-Pr-Cy5.5-ANG, Fig. 1) (8,13). All conjugates displayed a similar size (around 40 nm in diameter) and z potential (−30 to −40 mV) according to dynamic light scattering measurements and corroborated by cryo-transmission electron microscopy (TEM) images (further details regarding conjugate characterization such as dye/peptide loading can be found in table S1 and fig.…”

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

“…[62,63] Vicent and co-workers reported star-shaped polyglutamates, which self-assembled softly into nanostructures with applicability in drug delivery. [64,65] A hydrogel was prepared by crosslinked star block co-polypeptides. [66] Qiao and co-workers designed star-shaped poly(lysine-r-valine) as an efficient antimicrobial reagent to combat multidrug-resistant bacteria.…”