Extracellular Signal–Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury

Abstract

The upregulation of kidney injury molecule-1 (KIM-1) has been extensively studied in various renal diseases and following acute injury; however, the initial mechanisms controlling KIM-1 expression remain limited. In this study, KIM-1 expression was examined in mouse renal cell cultures and in two different models of acute kidney injury (AKI), ischemia reperfusion (IR)-induced and lipopolysaccharide (LPS)-induced sepsis. KIM-1 mRNA increased in both AKI models, and pharmacological inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling attenuated injury-induced KIM-1 expression in the renal cortex. Toll-like receptor 4 knockout (TLR4KO) mice exhibited reduced ERK1/2 phosphorylation and attenuated KIM-1 mRNA after LPS exposure. TLR4KO mice were not protected from IR-induced ERK1/2 phosphorylation and upregulation of KIM-1 mRNA. Following renal IR injury, phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 and tyrosine 705 increased downstream from ERK1/2 activation. Because phosphorylated STAT3 is a transcriptional upregulator of KIM-1 and inhibition of ERK1/2 attenuated increases in STAT3 phosphorylation, we suggest an ERK1/2-STAT3-KIM-1 pathway following renal injury. Finally, ERK1/2 inhibition in naive mice decreased KIM-1 mRNA and nuclear STAT3 phosphorylation in the cortex, indicating homeostatic regulation of KIM-1. These findings reveal renal ERK1/2 as an important initial regulator of KIM-1 expression in IR and septic AKI and at a physiologic level.Proposed mechanism of IR, LPS, and ROS-induced renal damage that initiates ERK1/2 and STAT3 phosphorylation. STAT3 then binds to the KIM-1 promoter and increases KIM-1 mRNA. By preventing ERK1/2 phosphorylation following renal injury, STAT3 phosphorylation is decreased, leading to less phosphorylated STAT3 within the nucleus, and subsequently less KIM-1 mRNA increases post injury.

Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

“…Since ERK1/2 has been shown to regulate mouse KIM-1 expression physiologically and following ischemic and septic renal injury [26], we next examined whether palmitate-induced KIM-1 is also dependent on ERK1/2 activation. As shown in Figure 5A,B, pretreatment with U0126, a specific ERK1/2 inhibitor, resulted in a significant reduction of KIM-1 in palmitate-stimulated cells.…”

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

“…17 It is probable that some of the beneficial effects of ERK1/2 inhibition are due to effects on tubular cells. Indeed, trametinib has been shown to reduce tubular damage during ischemia/reperfusion injury 49,50 and sepsis. 50 Whether ERK1/2 pathway inhibition ameliorated tubular injury upon UUO in addition to suppressing myofibroblast expansion merits further investigation.…”

“…Indeed, trametinib has been shown to reduce tubular damage during ischemia/reperfusion injury 49,50 and sepsis. 50 Whether ERK1/2 pathway inhibition ameliorated tubular injury upon UUO in addition to suppressing myofibroblast expansion merits further investigation. Trametinib also attenuated AKT phosphorylation (Figure 2A), known to be activated downstream of TGF-b1 51 and induced by UUO.…”

Proximal Tubule β2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury

“…Deletion of PGC-1a, a key transcriptional regulator of MB, worsens RPTC injury, whereas its overexpression promotes MB to accelerate recovery (Tran et al, 2011(Tran et al, , 2016. Pharmacologic induction of MB accelerates the recovery of mitochondrial and renal function after AKI (Jesinkey et al, 2014;Collier et al, 2016;Collier and Schnellmann, 2017). Formoterol-treated mice lacking the b 2 AR in RPTC failed to recover mtDNA copy number, mitochondrial protein expression, and mitochondrial number and area after AKI.…”