Molecular differences in susceptibility of the kidney to sepsis-induced kidney injuryReport as inadecuate




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BMC Nephrology

, 18:183

Genetics

Abstract

BackgroundSeptic acute kidney injury affects 40–50% of all septic patients. Molecular differences between septic patients with and without acute kidney injury AKI are only poorly understood. Here, we investigated gene expression changes that differentiated the subjects who developed septic AKI from those who did not and coupled this approach with traditional parameters of renal physiology.

MethodsIn 15 anesthetized, mechanically ventilated and instrumented pigs, progressive sepsis was induced either by peritonitis or by continuous intravenous infusion of Pseudomonas aeruginosa. Animals received standard intensive care including goal-directed hemodynamic management. Analyses were performed on kidneys from sham operated animals, septic pigs without AKI, and pigs with septic AKI. Before, and at 12, 18 and 22 h of progressive sepsis, systemic and renal hemodynamics, cortex microcirculation and plasma IL-6 and TNF-α were measured. At 22 h whole kidney expression of pre-selected genes was analyzed by quantitative Real Time PCR.

ResultsAnimals with septic AKI had systemic hemodynamic phenotype normo- or hyperdynamic comparable with non-AKI subjects, but demonstrated higher plasma levels of cytokines, an increase in renal vascular resistance and early fall in cortical microcirculatory blood flow. The genes whose expression discriminated septic AKI from non-AKI included Toll like receptor 4 up-regulated 2.7-fold, P = 0.04; Cyclooxygenase-2 up-regulated 14.6-fold, P = 0.01, Angiotensin II Receptor up-regulated 8.1-fold, P = 0.01, Caspase 3 up-regulated 5.1-fold, P = 0.02, Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha down-regulated 2-fold, P = 0.02.

ConclusionsIn this preliminary experimental study, kidney gene expression was profoundly different in animals that developed septic AKI as opposed to septic animals that did not. The biological functions of the genes differentially expressed support a role of inflammatory overstimulation coupled with metabolic and apoptotic molecular responses in early septic AKI. Cyclooxygenase-2 and angiotensin type 2 receptor-dependent downstream mechanisms appear fruitful targets for future mechanistic research.

KeywordsSepsis Acute kidney injury Animal models Gene expression AbbreviationsAGTR2Angiotensin II Receptor, Type 2

AKIAcute kidney injury

BAXBCL2-Associated X Protein

CASP3Caspase 3

HIF1alfaHypoxia inducible factor 1

HSP 27Heat shock protein 27

HSP70Heat shock protein

HSP90AA1Heat shock protein 90

HSPA5Heat shock cognate 70 kDa protein

NOS2Inducible nitric oxide synthase

PGC-1 alphaPeroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha

PGHS-2Cyclooxygenase-2

S-AKISepsis-induced acute kidney injury

TLR-2Toll like receptor 2

TLR-4Toll like receptor 4

TNF-αTumor necrosis factor alpha





Author: Martin Matejovic - Lenka Valesova - Jan Benes - Roman Sykora - Roman Hrstka - Jiri Chvojka

Source: https://link.springer.com/







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