Introduction:
The global prevalence of kidney patients exceeds 850 million, with Chronic Kidney Disease (CKD) reaching 9.5% of the world's population by 2024 which is particularly notable in Central and Eastern Europe. Focal and segmental glomerulosclerosis (FSGS) is one of the main factors contributing to the progression of end-stage renal disease. Studies on markers are essential to identify causes and to develop therapeutic targets. The MAPK family proteins are related with the progression of FSGS, however, the development of this cell signaling cascade is still uncertain. These family consists of the extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38. Activation by extracellular stimuli triggers a phosphorylation cascade involving various signaling pathways. The p38 protein plays a crucial role in the production of pro-inflammatory cytokines, cell survival/death and cytoskeleton stability. The EGR1 transcription factor is crucial in the regulation of cell survival, proliferation and death, as well as in fibrotic processes, making it an important marker of podocyte damage in glomerular. The aim of this study is to analyze how the ERK/p38MAPK and Egr-1 pathways interact in the signaling of GESF induced by Adriamycin (ADR), which may be important in clinical applications.
Methods:
8-week-old BALB/c mice received a single dose of ADR via the tail vein (10 mg/kg) and the control (CTL) group received 0.9% NaCl solution. Both groups were monitored for 28 days and then euthanized. Kidney function, morphology and protein expression were evaluated. Immortalized mouse podocytes were treated by ADR [10-6 M] for 15 min, 30min, 6h and 24 h (n=6) followed by protein expression Statistical analyses were done using t test with Welch correction.
Results:
The ADR treatment induced a body weight loss when compared to the CTL group. [g (CTL: 2.00±1.05 vs. -2.75±2.71, p=0.0013). Food and water intake weren’t different between the groups. The treatment didn’t change the creatinine and urea plasmatic levels when the groups were compared. On the other hand, ADR showed a higher urinary flow rate than the CTL animals [µL/min (CTL: 0.11±0.06 vs. ADR: 0.91±0.38, p=0.0005). Regarding glomerular morphology, the glomerulosclerosis index obtained results (GSI: (n=10, CTL: 0,11+-0,09 vs. n=8 ADR: 2,23+-0,74, p= <0.0001). About protein expression, the p38MAPK was increased after ADR treatment for 15 min, 6h and 24h [AU, 15 min: (CTL: 0.57±0.15 vs. ADR: 2,52±1,43, p= 0.0206), (6h: (CTL: 0.43±0.20 vs. ADR: 0.85±0.18, p=0.0040), (24h: (CTL: 0.45±0.35 vs. ADR: 1.46±0.57). ERK1/2 expression was increased too in 15min and 24h [AU, 15 min: (CTL: 0.20±0.08 vs. ADR: 1.15±1,0.09, p= <0.000), AU, 24h: (CTL: 0.52±0.16 vs. ADR: 1.20±0.32, p=0.0024). In addition, the EGR1 was significantly increased after 24h, 6h and 1h [AU, 24h: (CTL: 0.13±0.06 vs. ADR: 0.93±0.16, p= 0,0009), AU, 6h: (CTL: 0.26±0.15 vs. ADR: 0.99±0.19, p=0.0002), AU, 1h: (CTL: 0.14±0.07 vs. ADR: 1.01±0.15, p=<0,0001).
Conclusions:
Our results indicate that the activation of the EGR1 transcription factor goes hand in hand with the activation of p38 and ERK1/2 in the development of FSGS. Therefore, possible methods for inhibiting MAPK activation could help prevent the overexpression of nuclear EGR1, thus avoiding the accumulation of extracellular matrix and the loss of podocyte adhesion.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.