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Positively charged Ce-doped polypyrrole nanoparticles ameliorate acute kidney injury by endo-exogenous regulation of oxidative stress

ABSTRACT: Acute kidney injury (AKI) remains a critical clinical challenge with rapid renal function decline and limited therapeutic options. Mitochondrial reactive oxygen species (ROS)-induced oxidative stress drives AKI progression. This study develops a novel nanomedicine strategy utilizing cerium-doped polypyrrole (CePPy) nanoparticles to target ischemia-reperfusion injury-induced AKI. Synthesized via a green, one-step method, CePPy shows broad-spectrum antioxidant properties, and its positive surface charge enhances renal uptake and therapeutic efficacy compared to negatively charged counterparts. We demonstrate that positively charged CePPy (designated (+)CePPy), preferentially accumulates in the mitochondria of injured proximal tubular epithelial cells (PTECs) through transcytosis from peritubular capillaries. The (+)CePPy exhibits strong ROS scavenging capabilities as an exogenous antioxidant, and bolsters endogenous mitochondrial defenses via Mpv17l-dependent mechanisms, demonstrating significant protective effects in AKI models and preventing progression to chronic kidney disease. Furthermore, PTECs eliminate nearly 90% of CePPy within 14 days, indicating exceptional clearance efficiency. These findings highlight the potential of (+)CePPy as a promising therapeutic strategy for AKI, with significant implications for clinical translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE313051 | GEO | 2026/05/12

REPOSITORIES: GEO

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Project description:Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for development of acute kidney injury (AKI). Although bone marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated TG-BMSCs from young, end organ disease-free rats with increased RAS activation (human angiotensinogen/renin double transgenic rats; dTGR) that eventually develop hypertension and die of end-organ damage and kidney failure at 8-weeks-of-age. Control cells were isolated from wild-type Sprague-Dawley rats (SD-BMSCs). Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells’ therapeutic efficacy was evaluated in a rat model of acute ischemia-reperfusion-induced AKI. Serum urea and creatinine were measured at 24h and 48h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation (MCP-1, ED-1), and kidney injury (KIM-1, NGAL). TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration, and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast to the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by shift into a pro-inflammatory phenotype with mitochondrial dysfunction. A comparison of transcriptome of a bone marrow-derived stromal cells from a double-transgene rats compared to those from control rats

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Positively charged Ce-doped polypyrrole nanoparticles ameliorate acute kidney injury by endo-exogenous regulation of oxidative stress

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