miR-182-5p Inhibition Ameliorates Ischemic Acute Kidney Injury

Abstract

Acute kidney injury (AKI) remains a major clinical event with high mortality rates. We previously identified renal miR-182 as the main driver of post-transplantation AKI. Therefore, we tested the causal inference of miR-182 by inhibiting its renal expression in vivo. In 45 rats AKI was induced by right nephrectomy and contralateral clamping of the renal pedicle for 40 minutes. Systemically administered antisense oligonucleotide (ASO) inhibited miR-182 in the kidneys up to 96 hours. The maximum creatinine elevation was on day 2 after injury (mg/dL; median and interquartile range): ASO 2.5mg/kg: 1.9 (1.3; 3.2), ASO 25mg/kg: 2.8 (0.7; 5.0), mismatch oligonucleotide (MM) 25mg/kg: 5.7 (5,0; 5.8), saline: 4.4 (3.5; 5.8) (P = 0.016, analysis of variance). Blinded semiquantitative histologic evaluation of renal biopsies showed better preserved morphology in both ASO groups than saline- and MM-treated kidneys (median and interquartile range of overall injury scores): ASO both concentrations 1 (1, 1), saline 3 (3, 3) and MM 3 (3, 3) (P< 0.001, analysis of variance). ASO facilitated cell proliferation, metabolism, and angiogenesis on a genome-wide level. ASO when applied in normothermic kidney machine perfusion reduced renal miR-182 expression by more than two magnitudes. In summary, we showed that in vivo inhibition of miR-182 by ASO improved kidney function and morphology after AKI. This technique may be applicable to reduce the high rate of AKI in the human renal transplantation setting.

MicroRNA-668 represses MTP18 to preserve mitochondrial dynamics in ischemic acute kidney injury

“…We and others further identified the microRNA species with significant changes in expression during ischemic AKI (24,25). More recent studies have examined the role and regulation of some of these microRNAs in ischemic AKI, including miR-494, -21, -126, -687, -150, -489, and -17-5p (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Interestingly, some of the microRNAs promote ischemic AKI, but others play renoprotective roles (32,36,40).…”

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes

“…LETO (n = 13), OLETF (n = 12), CQ-treated LETO (LETO+CQ, n = 9), and CQ-treated OLETF (OLETF+CQ, n = 10) underwent nephrectomy of the right kidney followed by 30-min ischemia/24 h-reperfusion in the left kidney. We employed this one-kidney one-I/R model as in earlier studies 32–34 because, in pilot experiments, bilateral renal I/R resulted in a large data variation between experiments in our hands (data not shown). The unilateral renal I/R method has an advantage that the right kidney removed before I/R of the contralateral kidney serves as control tissue before I/R.…”

Dopamine in transplantation: Written off or comeback with novel indication?

“…38 Other strategies at the pre-clinical stage targeting donor organs rather than the recipients focused on cell-bound complement, 39 coagulation inhibitors, 40 and the use of antisense nucleotides for amelioration of ischemia-reperfusion injury. 41,42 A recent donor intervention trial from the US found that the induction of mild hypothermia in the DBD reduces delayed graft function after kidney transplantation. 43 Preliminary observational data suggest that low-dose dopamine may provide an additive effect to the benefit of a lower core body temperature.…”