Contribution of the p38MAPK Signaling Pathway and the Egr-1 Transcription Factor in Glomerulosclerosis

Background: Chronic kidney disease (CKD), characterized by the progressive loss of kidney function, is one of the most serious public health problems. Its progression is followed by focal and segmental glomerulosclerosis (FSGS). This study aims to look at how ERK/p38MAPK and Egr-1 pathways interact in the signaling of Adriamycin (ADR)-induced FSGS. 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 and 24 h followed by protein expression Statistical analyses were done using t test with Welch correction. Results: The ADR treatment did not change the creatinine and urea plasmatic levels when compared with the CTL group. [Creatinine,mg/dL: (CTL: 0.23±0.05 vs. ADR:0.25±0.12, p= 0.7427), Urea, mg/dL: (CTL: 59.60±4.97 vs. ADR: 70.76±60.39, p=0.6181). 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). 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 were not different between the groups. [Food intake, g/24h (CTL: 5.60±1.50 vs. ADR: 6.25±1.66, p=0.4054), (Water intake, ml/24h (CTL: 2.40±0.84 vs. ADR: 3.62±1.50, p=0.0655). About podocyte protein expression, the p38MAPK was increased after ADR treatment for 15 min or 24h[arbitrary units, 15 min: (CTL: 0.5130±0.13 vs. ADR: 3.16±1.35, p= 0.0289), (arbitrary units, 24h: (CTL: 0.30±0.12 vs. ADR: 1.61±0.54, p=0.0142). However, the Egr-1 was significantly increased after 24 h of treatment with ADR [10-6M][AU, 24h: (CTL: 0.13±0.06 vs. ADR: 0.93±0.16, p= 0,0009, n=4). About the glomeruloesclerosis index (GSI), there were significant differences between the groups. [GSI: (CTL: 0,04±0,05 vs. 2,39±0,81, p=0,0101)]. Conclusion: Our results indicate that the activation of p38MAPK by an insult corroborates the activation of the nuclear transcription factor Egr-1 and thus the development of FSGS as shown in the treated animals with ADR. Funding: Government Support – Non-U.S.