Attenuation of Acute Renal Injury After the Post-resuscitation Administration of Doxycycline in Surviving Newborn Piglets With Severe Hypoxia-Reoxygenation

Abstract

Background: Asphyxiated neonates often have myocardial dysfunction and renal insufficiency. Previously we demonstrated that doxycycline improved cardio-renal function through matrix metalloproteinase (MMP)-2 inhibition in an acute swine model of neonatal hypoxia-reoxygenation. The prolonged cardio-renal protective effects of doxycycline in neonates still remained unknown. We therefore hypothesized that the protective effects of doxycycline persisted in surviving subjects. Methods: Newborn piglets were instrumented and subjected to 1 h of hypoxia followed by reoxygenation with 21–25% oxygen and observed for 4 days. Intravenous doxycycline (30 mg/kg) or normal saline (1 mL, saline-control group) was given at 5 min of reoxygenation ( n = 8/group) in a randomized, blinded fashion. Sham-operated piglets ( n = 5) received no hypoxia-reoxygenation. At 96 h after reoxygenation, the left ventricular function was assessed by Millar® catheter. Renal injury was investigated by measuring plasma creatinine, urinary N-acetyl-D-glucosaminidase activity, renal tissue lactate and MMP-2 activity. Results: Both hypoxia-reoxygenation groups had similar hypoxic stress with severe lactate acidosis, and hemodynamic recovery. Doxycycline-treated piglets had higher urine output with lower urine N-acetyl-D-glucosaminidase, plasma creatinine, and renal MMP-2 activity (vs. saline-controls; all p < 0.05). These markers were all negatively correlated with urine output. Conclusions: In newborn piglets surviving hypoxia-reoxygenation, we observed a weak but significant and persistent attenuation of renal injury and improved recovery with the post-resuscitation administration of doxycycline.

Epigenetic Regulation of the N-Terminal Truncated Isoform of Matrix Metalloproteinase-2 (NTT-MMP-2) and Its Presence in Renal and Cardiac Diseases

“…Cardiotoxicity was attenuated by MMP inhibitors ( Chan et al, 2021 ). Regarding MMPs inhibitors, they are shown to be protective in different models of renal and cardiac diseases, including type 1 diabetes ( Yaras et al, 2008 ), in vivo renal injury ( Labossiere et al, 2015 ; Lee T. F. et al, 2019 ), and other models of cardiac injury and cardiovascular dysfunction ( Kandasamy et al, 2010 ; Rizzi et al, 2010 ; Guimaraes et al, 2011 ; Castro et al, 2012 ). In this context, FL-MMP-2 and NTT-MMP-2 are relevant targets of pharmacological intervention.…”

miR‐302a‐3p targets FMR1 to regulate pyroptosis of renal tubular epithelial cells induced by hypoxia–reoxygenation injury

“…AKI is a widespread clinical condition with many aetiologies and is directly related to short‐ and long‐term impairment and mortality of patients, with a huge economic burden (Jha et al., 2021; L. Yang, 2019). Kidney is the first organ damaged by hypoxic insult due to regional vasoconstriction (T. F. Lee et al., 2019). Hypoxia is predominant in the pathogenesis of AKI under diverse clinical settings (Heyman et al., 2019).…”

“…damaged by hypoxic insult due to regional vasoconstriction (T. F. Lee et al, 2019). Hypoxia is predominant in the pathogenesis of AKI under diverse clinical settings (Heyman et al, 2019).…”