Plasma Concentrations of Extracellular DNA in Acute Kidney Injury

Jordanka Homolová, Ľubica Janovičová, Barbora Konečná, Barbora Vlková, Peter Celec, Ľubomíra Tóthová, Janka Bábíčková, Jordanka Homolová, Ľubica Janovičová, Barbora Konečná, Barbora Vlková, Peter Celec, Ľubomíra Tóthová, Janka Bábíčková

Abstract

Current diagnostic methods of acute kidney injury (AKI) have limited sensitivity and specificity. Tissue injury has been linked to an increase in the concentrations of extracellular DNA (ecDNA) in plasma. A rapid turnover of ecDNA in the circulation makes it a potential marker with high sensitivity. This study aimed to analyze the concentration of ecDNA in plasma in animal models of AKI. Three different fractions of ecDNA were measured-total ecDNA was assessed fluorometrically, while nuclear ecDNA (ncDNA) and mitochondrial DNA (mtDNA) were analyzed using quantitative real-time PCR. AKI was induced using four different murine models of AKI-bilateral ureteral obstruction (BUO), glycerol-induced AKI (GLY), ischemia-reperfusion injury (IRI) and bilateral nephrectomy (BNx). Total ecDNA was significantly higher in BUO (p < 0.05) and GLY (p < 0.05) compared to the respective control groups. ncDNA was significantly higher in BUO (p < 0.05) compared to SHAM. No significant differences in the concentrations of mtDNA were found between the groups. The plasma concentrations of different fractions of ecDNA are dependent on the mechanism of induction of AKI and warrant further investigation as potential surrogate markers of AKI.

Keywords: cell free DNA; ischemia; nephrectomy; uremia; ureteral obstruction.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Renal function and histopathological assessment of mice with acute kidney injury (AKI). Bilateral ureteral obstruction: (a) creatinine; (b) BUN; (c) left panel—normal renal architecture, right panel—tubular dilation and atrophy. Glycerol-induced AKI: (d) creatinine; (e) BUN; (f) left panel—normal renal architecture, right panel—tubular atrophy and proteinuric casts. Ischemia–reperfusion injury: (g) creatinine; (h) BUN; (i) left panel—normal renal architecture, right panel—tubular atrophy and dilation, epithelial cell necrosis and cell shedding, and proteinuric casts. Bilateral nephrectomy: (j) creatinine. Overview of the preparation of the individual models (k). BUO—bilateral ureteral ligation, BUN—blood urea nitrogen, GLY—glycerol-induced AKI, UNx—unilateral nephrectomy, IRI—ischemia–reperfusion injury, BNx—bilateral nephrectomy. ** denotes p < 0.01, *** denotes p < 0.001. Data are presented as mean + SD. Histological images show periodic acid Schiff stain (PAS), magnification 400x.
Figure 2
Figure 2
Total ecDNA measured in plasma of mice with acute kidney injury (AKI). (a) Bilateral ureteral obstruction. (b) Glycerol-induced AKI. (c) Ischemia–reperfusion injury. (d) Bilateral nephrectomy. * denotes p < 0.05. Data are presented as mean + SD. BUO—bilateral ureteral ligation, GLY—glycerol-induced AKI, UNx—unilateral nephrectomy, IRI—ischemia–reperfusion injury, BNx—bilateral nephrectomy.
Figure 3
Figure 3
Nuclear ecDNA (ncDNA) measured in plasma of mice with acute kidney injury (AKI). (a) Bilateral ureteral obstruction. (b) Glycerol-induced AKI. (c) Ischemia–reperfusion injury. (d) Bilateral nephrectomy. * denotes p < 0.05. Data are presented as mean + SD. BUO—bilateral ureteral ligation, GLY—glycerol-induced AKI, UNx—unilateral nephrectomy, IRI—ischemia–reperfusion injury, BNx—bilateral nephrectomy.
Figure 4
Figure 4
Mitochondrial ecDNA (mtDNA) measured in plasma of mice with acute kidney injury (AKI). (a) Bilateral ureteral obstruction. (b) Glycerol-induced AKI. (c) Ischemia–reperfusion injury. (d) Bilateral nephrectomy. Data are presented as mean + SD. BUO—bilateral ureteral ligation, GLY—glycerol-induced AKI, UNx—unilateral nephrectomy, IRI—ischemia–reperfusion injury, BNx—bilateral nephrectomy.

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