Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor

Abstract

The β-common receptor (βcR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the βcR. In young (2 months old) C57BL/6 wild-type and βcR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1 h after lipopolysaccharide in wild-type but not in βcR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3β, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-κB. All these effects of EPO were lost in βcR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and βcR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24 h, which was attenuated by EPO treatment 1 h post cecal ligation and puncture in wild-type mice but not in βcR knockout mice. Thus, activation of the βcR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO.

Progranulin protects against endotoxin-induced acute kidney injury by downregulating renal cell death and inflammatory responses in mice

“…As a natural filter of blood and the first line of defense in our body, the kidney is a direct target of LPS-mediated inflammatory injury [30]. Clinically, septic AKI is characterized by deregulated physiological responses, including low renal blood flow, glomerular filtration rate, and hypotension [11]; abnormal renal function with increased BUN and creatinine levels [31]; and histopathological changes of kidney, such as tubular cell necrosis and apoptosis, sloughing, vacuolization and tubular dilatation [11,32].…”

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

“…Very recently, the use of βcR knockout mice has enabled us and others to confirm that the activation of the heteromeric EPOR-βcR complex is indeed essential for the reduction of both kidney and cardiac dysfunction associated with sepsis, as well as in producing long-term relief of neuropathic pain (Swartjes et al, 2011;Coldewey et al, 2013;Khan et al, 2013).…”

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

“…Older patients are more frequently affected by sepsis, and the treatment at intensive care units is, except for early administration of antibiotics, mostly of a supportive nature, including vasopressor therapy and fluid replenishment (25). In this study, we simulated these conditions by performing CLP in 8-mo-old mice treated with a large spectrum of antibiotic and fluids (26,27). Fpr2/3 −/− mice developed longer lasting macroscopic signs of severe sepsis, as evident from 24 h of hypothermia, than WT animals.…”