Engineered nanoplex mediated targeted miRNA delivery to rescue dying podocytes in diabetic nephropathy
Nidhi Raval1, Piyush Gondaliya1, Vishakha Tambe1
1National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Palaj, Opp. Air Force Station, Gandhinagar 382355, Gujarat, India.
Abstract:
MicroRNAs (miRNA) is vital for gene expression regulation and normal kidney function. Mainly, miRNA-30a is responsible for the homeostasis of podocytes. In the diabetic nephropathic condition, miRNA-30a is directly and primarily suppressed by hyperglycemic kidney induced Notch signaling pathway leads to podocyte damage and apoptosis. Thus, transferring the exogenous miRNA-30a to podocytes might improve albuminuria as well as podocytes injury. The deprived stability, poor targetability, and low specificity in vivo are critical limitations to attain this objective. This investigation reports the specific and efficient delivery of miRNA-30a mimic via cyclo(RGDfC)-gated polymeric-nanoplexes with dendrimer templates to alleviate podocyte conditions. The nanoplexes able to protect RNase enzyme and to exhibit greater cellular uptake viaαvβ3 receptor selective binding in HG treated podocytes. The nanoplexes up-regulated the expression level of miRNA-30a and repress the elevated Notch-1 signaling in HG exposed podocytes. The critical results of in vivo experimentation attribute marked suppression of Notch-1 in streptozotocin (STZ) induced diabetic C57BL/6 mice and reduced glomerular expansion and fibrosis in the glomerular area. Developed nanoplexes represents an efficient platform for the targeted delivery of exogenous miRNA to podocytes. The approach developed herein could be extrapolated to other gene therapeutics and other kidney-related diseases.
Insights
This study developed novel nanoplexes for targeted delivery of miRNA-30a to protect kidney podocytes. These nanoplexes show promise in treating diabetic nephropathy by reducing kidney damage and fibrosis.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Nephrology
Background:
- MicroRNAs (miRNA) regulate gene expression and kidney function, with miRNA-30a crucial for podocyte homeostasis.
- Diabetic nephropathy involves hyperglycemic suppression of miRNA-30a via Notch signaling, leading to podocyte damage.
- Limitations in miRNA delivery, including stability and specificity, hinder therapeutic potential.
Purpose of the Study:
- To develop a targeted delivery system for miRNA-30a mimic to alleviate podocyte injury in diabetic nephropathy.
- To investigate the efficacy of cyclo(RGDfK)-gated polymeric-nanoplexes with dendrimer templates for miRNA-30a delivery.
Main Methods:
- Engineered cyclo(RGDfK)-gated polymeric-nanoplexes with dendrimer templates for miRNA-30a mimic delivery.
- Evaluated nanoplex protection against RNase and cellular uptake via αvβ3 receptor binding in high glucose (HG)-treated podocytes.
- Assessed in vitro effects on miRNA-30a levels and Notch-1 signaling.
- Conducted in vivo studies in streptozotocin (STZ)-induced diabetic mice.
Main Results:
- Nanoplexes demonstrated RNase protection and enhanced cellular uptake in HG-treated podocytes.
- In vitro, nanoplexes upregulated miRNA-30a and repressed Notch-1 signaling.
- In vivo, nanoplexes significantly suppressed Notch-1, reduced glomerular expansion, and mitigated fibrosis in diabetic mice.
Conclusions:
- Developed nanoplexes provide an efficient platform for targeted delivery of exogenous miRNA to podocytes.
- This approach offers a potential therapeutic strategy for diabetic nephropathy and other kidney diseases.
- The technology may be applicable to other gene therapeutics for renal conditions.
