Meprin β Activity Modulates Cellular Proliferation via Trans-Signaling IL-6-Mediated AKT/ERK Pathway in Ischemia/Reperfusion (IR)-Induced Kidney Injury
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Abousaad, Shaymaa, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States
- Ahmed, Faihaa, NC State University, Raleigh, North Carolina, United States
- Abouzeid, Ayman, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States
- Ongeri, Elimelda Moige, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States
Inflammation plays a central role in the progression of kidney injury induced by ischemia/reperfusion (IR). Meprin metalloproteinases have been implicated in the pathophysiology of IR-induced kidney injury. We previously showed that meprin β modulates cellular survival (BCL-2) through IL-6/JAK/STAT signaling pathway in IR-induced kidney injury. However, it’s not known how meprin β modulation of the IL-6 signaling pathway impacts the cellular proliferation in IR-induced AKI. IL-6 trans-signaling induces proliferation through either MAPK/ERK or PI3K/AKT pathway or in crosstalk with AKT/ERK. PCNA is a cellular proliferation marker that is induced through activation of the IL-6 signaling pathway. The goal of the current study was to determine how meprin β modulation of the IL-6 signaling pathway impacts downstream cellular proliferation in IR-induced kidney injury.
We used the unilateral IR as a model of renal inflammation in wild-type (WT) and meprin β knockout (βKO) male mice, with the contralateral kidneys serving as controls. The mice were sacrificed at 96 h post-IR, and kidney tissue processed for evaluation by RT-PCR and immunohistochemistry. Statistical analysis of data utilized two-way ANOVA.
Our PCR data showed significant increase in mRNA levels for IL-6 and PCNA in WT and βKO mice at 96 h-post IR when compared to WT control kidneys. Immunohistochemical data showed significant increases in IL-6, PCNA, p-AKT and p-ERK in select tubules in both genotypes at 96 h post-IR compared to control kidneys. Data from immunofluorescence of kidney tissues showed that the levels of IL-6, PCNA, p-AKT and p-ERK were higher in meprin β-expressing proximal tubules (PTs), at 96 h post-IR when compared to the distal kidney tubules (DTs), which lack meprins. High levels of IL-6 were also present in the lumen of PTs and DTs from WT and βKO kidneys at 96 h post-IR, suggesting increased release into filtrate and subsequently into urine. However, high levels of PCNA, p-AKT and p-ERK were present in the lumen of PTs only from both genotypes at 96 h post-IR.
In conclusion, our data shows that meprin β activity modulates cellular proliferation via trans-signaling IL-6-mediated AKT/ERK pathway in IR-induced kidney injury.
- Other NIH Support