Redox nanomedicine ameliorates chronic kidney disease (CKD) by mitochondrial reconditioning in mice

Abstract

Targeting reactive oxygen species (ROS) while maintaining cellular redox signaling is crucial in the development of redox medicine as the origin of several prevailing diseases including chronic kidney disease (CKD) is linked to ROS imbalance and associated mitochondrial dysfunction. Here, we have shown that a potential nanomedicine comprising of Mn3O4 nanoparticles duly functionalized with biocompatible ligand citrate (C-Mn3O4 NPs) can maintain cellular redox balance in an animal model of oxidative injury. We developed a cisplatin-induced CKD model in C57BL/6j mice with severe mitochondrial dysfunction and oxidative distress leading to the pathogenesis. Four weeks of treatment with C-Mn3O4 NPs restored renal function, preserved normal kidney architecture, ameliorated overexpression of pro-inflammatory cytokines, and arrested glomerulosclerosis and interstitial fibrosis. A detailed study involving human embryonic kidney (HEK 293) cells and isolated mitochondria from experimental animals revealed that the molecular mechanism behind the pharmacological action of the nanomedicine involves protection of structural and functional integrity of mitochondria from oxidative damage, subsequent reduction in intracellular ROS, and maintenance of cellular redox homeostasis. To the best of our knowledge, such studies that efficiently treated a multifaceted disease like CKD using a biocompatible redox nanomedicine are sparse in the literature. Successful clinical translation of this nanomedicine may open a new avenue in redox-mediated therapeutics of several other diseases (e.g., diabetic nephropathy, neurodegeneration, and cardiovascular disease) where oxidative distress plays a central role in pathogenesis.

Nanoparticles in the diagnosis and treatment of vascular aging and related diseases

“…Notably, four weeks of C-Mn 3 O 4 NPs treatment effectively restored renal function, mediated recovery of kidney architecture, improved expression of pro-inflammatory factors, and suppressed glomerulosclerosis and interstitial fibrosis in cisplatin-induced chronic kidney disease mice model. 383 …”

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…Targeting NAD + redox balance has been suggested as a strategy for fighting cisplatin-induced kidney injury [ 18 , 60 ]. Therefore, there has been an increasing interest in studying redox biochemistry and NAD + redox signaling in the pathogenesis of cisplatin renal toxicity [ 32 , 61 , 62 , 63 , 64 ]. The major NAD + -dependent redox enzymes that may be involved in cisplatin-induced kidney injury are shown in Figure 4 .…”

Current Strategies and Potential Prospects for Nanoparticle-Mediated Treatment of Diabetic Nephropathy

“…Biocompatible transition metal oxide NPs are highly sought after for their wide range of remarkable properties and applications, particularly their electron-donating and accepting activity, which is considered the best type of NP to maintain the balance of the redox potential of cellular mitochondria. 77 C-Mn 3 O 4 NP has become one of the least expensive and most effective materials for oxidative stress, owing to its free radical scavenging activity and good biocompatibility. C-Mn 3 O 4 NP is autocatalytic and has protective effects through preventing mitochondrial permeability transition pore (mPTP) opening and ATP depletion.…”

“… C-Mn 3 O 4 NPs long-term attenuate renal injury and tubuleintestinal fibrosis showing not any toxicological implications. A. Adhikari et al 77 Adhikari et al 79 ZnO NPs ZnO Kidney ZnONP decreases the expression of TGF‐β1, collagen IV, and fibronectin and increases the expression of MMP‐9 in the diabetic kidney with low toxicity. ZnONPs can improve renal function, by inhibiting renal fibrosis, oxidative stress, inflammation, and abnormal angiogenesis and the ameliorating podocyte injury to ameliorate the renal damage.…”