TY - JOUR
T1 - Lipoxins regulate the early growth response-1 network and reverse diabetic kidney disease
AU - Brennan, Eoin P.
AU - Mohan, Muthukumar
AU - McClelland, Aaron
AU - Tikellis, Christos
AU - Ziemann, Mark
AU - Kaspi, Antony
AU - Gray, Stephen P.
AU - Pickering, Raelene
AU - Tan, Sih Min
AU - Tasadaque Ali-Shah, Syed
AU - Guiry, Patrick J.
AU - El-Osta, Assam
AU - Jandeleit-Dahm, Karin
AU - Cooper, Mark E.
AU - Godson, Catherine
AU - Kantharidis, Phillip
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.
AB - Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE-/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renalproinflammatory/profibrotic signals (TNF-α, IL-1β,NF-κB). Indiabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response-1 [EGR-1]) networks activatedindiabetes andregulatedby LXs. Inculturedhuman renal epithelial cells, treatment with LXs attenuated TNF-α-driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.
UR - http://www.scopus.com/inward/record.url?scp=85046351735&partnerID=8YFLogxK
U2 - 10.1681/ASN.2017101112
DO - 10.1681/ASN.2017101112
M3 - Article
AN - SCOPUS:85046351735
SN - 1046-6673
VL - 29
SP - 1437
EP - 1448
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 5
ER -