Redox medicine for the treatment of chronic kidney disease

Jeenisha Dabreo Rumao

A new study performed by a team of researchers from various parts of India, Saudi Arabia, and Egypt shows that citrate-functionalized Mn3O4 nanoparticles can effectively treat chronic kidney disease.

An illustration explaining the potential of nanodrugs in the treatment of chronic kidney disease.
An illustration explaining the potential of nanodrugs in the treatment of chronic kidney disease. 

Chronic kidney disease (CKD) is a serious medical condition that is characterized by a progressive decline in kidney function. Oxidative stress (often originating from infection, pollution, stress, and irregular lifestyle) plays an important role in renal damage; it is characterized by increased intracellular levels of reactive oxygen species (ROS), which are free radicals generated as a by-product of oxidation. ROS is linked with tissue damage, inflammation and increase in the risk of degenerative diseases. 

Mitochondria are called the powerhouse’ of the cell and generate adenosine triphosphate (ATP), which helps to preserve the cell structure. Moreover, mitochondria function as an important regulator of ROS. The ROS-regulating mitochondria are highly susceptible to damage due to oxidative stress. 

In order to maintain the cellular balance of these oxidative molecules, a safe, symptomatic, and effective therapeutic strategy is needed. A previous report suggests that metal oxide nanoparticles with electron-donating and accepting potential exhibit antioxidant activity by preventing the damage caused by free radicals to cells. In this context, the researchers of the current study were keen on exploring the therapeutic potential of citrate-functionalized manganese oxide (Mn3O4) nanoparticles (C‑Mn3O4 NPs). The selection of this C‑Mn3O4NP complex can be attributed to its role in redox regulation and prevention of mitochondrial damage.

Based on this, cellular studies were conducted using human embryonic kidney (HEK 293) cells. During in vitro studies, it was observed that the C‑Mn3O4 NP complex preserved normal cell architecture by maintaining redox balance in the cells. Moreover, it helped to restore the mitochondrial membrane potential by inhibiting the stimuli that trigger apoptosis (cell death). This, in turn, increased the cell viability index. 

Explaining the course of the research, the lead author, Aniruddha Adhikari, Department of Chemical, Biological and Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Kolkata, says, There is always a gap in the efficacies of a pharmacological agent tested between cellular and animal models. As limited bioavailability, non-specific biodistribution, or unwanted metabolism often restrict the in vivo use of a cytoprotective agent, we evaluated the potential of C‑Mn3O4 NPs by conducting animal studies.” 

In this regard, for in vivo studies, the cisplatin-induced C57BL/​6j mouse model of CKD was used. The study results showed that the C‑Mn3O4 NP complex exhibited a scavenging activity against ROS in the mitochondria. It inhibited opening of the mitochondrial permeability transition pore, and ATP depletion, thereby preventing mitochondrial dysfunction. As a result, the morphology and physiological function of the kidney were maintained. This was indicated by the fact that the levels of CKD markers (serum urea, plasma creatinine, increased blood urea nitrogen and glomerular filtration rate) returned to homeostatic conditions. Additionally, the nanoparticles efficaciously mitigated the severe inflammatory responses originating from CKD. While explaining the therapeutic mechanism of the nanoparticles, Adhikari indicates that, The findings suggest that both the mechanisms (ROS scavenging and mitochondrial protection) take place simultaneously.”

On further exploring the therapeutic domain, it is seen that the NP complex can be developed as a nano-drug because of its biocompatibility and pharmacokinetic properties. The C‑Mn3O4 nanoparticles are known to enter the kidney — crossing the glomerular filtration barrier, which is a highly-specialized size and charge filtration interface for blood — and reside there, exhibiting a therapeutic mechanism. However, understanding the internalization of these nanoparticles and their molecular mechanism within the cells is very important before clinical translation. 

Adhikari states that, As CKD is known to be caused due to redox imbalance in the mitochondria, our nanoparticle complex proves to be an effective redox medicine which improves renal function by preserving and maintaining mitochondrial integrity.”

Commenting on the relevance of this study, Prantar Chakrabarti, Director of Haematology and Bone Marrow Transplant at AMRI Hospital, Kolkata, says, This research delves into a territory where there was limited success in therapeutics. Here, the researchers have looked at the problem from a different perspective. Therefore, this is novel research with great potential.” Further, about the future scope of the study, he adds that, As physicians, we are concerned about the safety of the patients and therefore, it is crucial to determine the long-term effects on the haematological levels.”

Written By

Jeenisha is biotechnology postgraduate pursuing her passion for science as a microbiologist. She believes that writing will help her develop a better insight into the field and aid in bridging the gap between research and communication.