Minyi Chen
Dr. David Sheikh-Hamad’s Lab
Stanniocalcin-1 protects ischemia/reperfusion kidney injury
BACKGROUND
In humans, acute kidney injury is highly prevalent; and the associated mortality rate remains high (up to 50%).
Ischemia/reperfusion (I/R) kidney injury, is a major cause of renal failure in both native and transplanted organs.
Mouse/rat experimental I/R kidney injury is a model for human I/R kidney injury. It is associated with phenomenon:decreased urine output and Glomerular Filtration
Rate(GFR); inflammation; tubular cell injury, characterized by vacuolization, cell
necrosis, and hyaline cast formation; full recovery is complete within 8 days.
Mechanism of free radical generation in ischemia reperfusion injury
Bulkey, G. B. Br. J. cancer, 1987
STANNIOCALCIN-1 (STC1) EFFECTS ON: ROS; ENDOTHELIAL AND MACROPHAGE FUNCTION
STC1 decreases superoxide generation in macrophages, via UCP2-depenent pathway (Wang et al., J Leukoc Biol. 2009 86:981-8).
STC1 inhibits macrophage migration and response to
chemoattractants (Kanellis, J. et al. Am J Physiol Renal Physiol, 2004, 286: F356-F362).
STC1 blocks Tumour Necrosis Factor(TNF)-α-induced rise in endothelial monolayer permeability and decreases TNF-α-induced activation of Jun N-terminal Kinase(JNK), NF- κB, and superoxide in endothelial cells (Chen, C. et al. Arterioscler Thromb Vasc Biol 2008; 28:906-912).
STC1 inhibits T-cell and macrophage transmigration across IL-1β-treated endothelial monolayer (Chakraborty et al., Am J Physiol Renal Physiol. 2007;292:F895-904).
WT STC1
Superoxide generation in STC1 Tg and WT kidney under normal condition without clamping
Labeling with 5 uM MitoSOX Red
HYPOTHESIS
Stanniocalcin-1 protects from I/R kidney injury by modulating key factors in the pathogenesis of I/R. These include: Decreased Reactive Oxygen Species(ROS) generation; Endothelial protection – preservation of normal endothelial
permeability - decreasing trans-endothelial migration of macromolecules and inflammatory cells (macrophages and T-cells), into the kidney;
Direct inhibition of macrophages.
Decline in Creatinine clearance (CrCl) after I/R kidney injury in WT mice; but preservation of
normal CrCl in STC1 Tg mice
Reduce of kidney function indicated by Glomerular Filtration Rate(GFR);
Kidney morphology in WT and STC1 Tg mice after I/R kidney injury
loss of brush border membrane (arrowheads), cellular vacuolization (v),tubular dilatation (dt) with cast formation (c)
Preservation of normal vascular permeability in kidneys of STC1 Tg mice after I/R injury compared to WT mice
Increased T-cells and macrophages in kidney of WT mice after I/R injury; but no change is observed in
kidneys of STC1 Tg mice
Increased superoxide and hydroperoxide in WT kidneys 24h after I/R injury; but not in kidneys of
STC1 Tg mice
STC1 protects from I/R kidney injury through suppression of oxidant stress
STC1 Tg mice were given a single i.p. injection of saline or paraquat (12.5 mg/kg). qaraquat is the generator of superoxide. I/R mice were clamped 2h later than injection, and killed 24h, or 72h. (A) Superoxide, (B) hydroperoxide, (C) CrCl expressed , (D) PAS staining for morphology.
WT mice displayDecline in CrCl (Glomerular Filtration Rate) at the 72h to 40% of sham-treated controls.Tubular injury (vacuolization, cell necrosis and cast formation).Increased vascular permeabilityInfiltration with macrophages and T-cells starting from day 1 through day 8.Increased superoxide and hydrogen peroxide generation (c/w increased risk for injury).
STC1 Tg mice displayNo decrease of kidney function.No increase in superoxide and H2O2 production.No increase in vascular permeability.No increase in macrophage and T-cell infiltration after I/R.
Conclusion: Tg overexpression of STC1 protects from I/R kidney injury; STC1 is a potential therapeutic target for the prevention/treatment of ischemia-related kidney injury
Summary
ACKNOWLEDGEMENTS
David Sheikh-Hamad, MD.
Luping Huang, MD. PhD.
Tatiana Belousova, MD.
Jenny Pan, MD.
Roohi Khan, MD.
Yanlin Wang, MD. PhD.
Luan Truong, MD.
Funding support through the NIH
