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Title: Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway

Author
item PAN, JENNY SZU-CHIN - Baylor College Of Medicine
item HUANG, LUPING - Baylor College Of Medicine
item BELOUSOVA, TATIANA - Baylor College Of Medicine
item LU, LIANGHAO - Baylor College Of Medicine
item YANG, YONGJIE - Children'S Nutrition Research Center (CNRC)
item REDDEL, ROGER - University Of Western Ontario
item CHANG, ANDY - University Of Western Ontario
item JU, HUIMING - Baylor College Of Medicine
item DIMATTIA, GABRIEL - University Of Western Ontario
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)
item SHEIKH-HAMAD, DAVID - Baylor College Of Medicine

Submitted to: American Society of Nephrology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/13/2014
Publication Date: 1/13/2015
Citation: Pan, J., Huang, L., Belousova, T., Lu, L., Yang, Y., Reddel, R., Chang, A., Ju, H., Dimattia, G., Tong, Q., Sheikh-Hamad, D. 2015. Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway. American Society of Nephrology. 26(6):364-378.

Interpretive Summary: Many diseases are associated with increased free radical levels. For example, obesity and diabetes cause the elevation of free radical-associated damage in various tissues. Free radicals play a role in kidney injury. Stanniocalcin-1 (STC1) is a secreted protein that can suppress the formation of free radicals and ameliorate kidney injury. On the other hand, mice lacking the STC1 protein have more severe kidney injury. We found that STC1 activates a cellular signaling protein called AMPK, which is required for STC1 to inhibit kidney injury. STC1 activates AMPK to increase the amount of two proteins (SIRT3 and UCP2) which are known to reduce cellular free radical levels. In summary, we have demonstrated that STC1 functions through AMPK, SIRT3 and UCP2 to exert its protective effects on kidney injury. Therefore, we may develop therapeutic mechanisms to activate STC1 or its downstream components (AMPK, SIRT3 or UCP2) to treat diseases associated with free radical elevation.

Technical Abstract: AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R.