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. 2018;43(3):904-913.
doi: 10.1159/000490338. Epub 2018 May 30.

Tempol Protects Against Acute Renal Injury by Regulating PI3K/Akt/mTOR and GSK3β Signaling Cascades and Afferent Arteriolar Activity

Gensheng Zhang  1 , Qin Wang  1 , Wenwen Wang  2 , Minghua Yu  2 , Suping Zhang  1 , Nan Xu  1 , Suhan Zhou  1 , Xiaoyun Cao  1 , Xiaodong Fu  3 , Zufu Ma  4 , Ruisheng Liu  5 , Jianhua Mao  1 , En Yin Lai  6
Affiliations

Tempol Protects Against Acute Renal Injury by Regulating PI3K/Akt/mTOR and GSK3β Signaling Cascades and Afferent Arteriolar Activity

Gensheng Zhang et al. Kidney Blood Press Res. 2018.

Abstract

Background/aims: Free radical scavenger tempol is a protective antioxidant against ischemic injury. Tubular epithelial apoptosis is one of the main changes in the renal ischemia/reperfusion (I/R) injury. Meanwhile some proteins related with apoptosis and inflammation are also involved in renal I/R injury. We tested the hypothesis that tempol protects against renal I/R injury by activating protein kinase B/mammalian target of rapamycin (PKB, Akt/mTOR) and glycogen synthase kinase 3β (GSK3β) pathways as well as the coordinating apoptosis and inflammation related proteins.

Methods: The right renal pedicle of C57Bl/6 mouse was clamped for 30 minutes and the left kidney was removed in the study. The renal injury was assessed with serum parameters by an automatic chemistry analyzer. Renal expressions of Akt/mTOR and GSK3β pathways were measured by western blot in I/R mice treated with saline or tempol (50mg/kg) and compared with sham-operated mice.

Results: The levels of blood urea nitrogen (BUN), creatinine and superoxide anion (O2.-) increased, and superoxide dismutase (SOD) and catalase (CAT) decreased significantly after renal I/R injury. However, tempol treatment prevented the changes. Besides, I/R injury reduced renal expression of p-Akt, p-GSK3β, p-mTOR, Bcl2 and increased NF-κB, p-JNK and p53 in kidney, tempol significantly normalized these changes. In addition, renal I/R injury reduced the response of afferent arteriole to Angiotensin II (Ang II), while tempol treatment improved the activity of afferent arteriole.

Conclusion: Tempol attenuates renal I/R injury. The protective mechanisms seem to relate with activation of PI3K/Akt/mTOR and GSK3β pathways, inhibition of cellular damage markers and inflammation factors, as well as improvement of afferent arteriolar activity.

Keywords: Acute kidney injury; Afferent arteriole; Ischemia/reperfusion; Tempol.

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Conflict of interest statement

Disclosure Statement

The authors of this manuscript state that they do not have any conflict of interests and nothing to disclose.

Figures

Fig. 1.
Fig. 1.
The renal afferent arteriolar microperfusion.
Fig. 2.
Fig. 2.
Effects of tempol on renal function after renal I/R injury. (A) Effects of tempol on serum creatinine after renal I/R injury. (B) Effects of tempol on serum BUN after renal I/R injury. Data are expressed as mean ± SEM, (n=8), * p<0.05 vs sham group; # p<0.05 vs I/R group.
Fig. 3.
Fig. 3.
Effects of tempol on oxidative stress induced by renal I/R injury. SOD, CAT and O2- in kidney were expressed as mean ± SEM, (n=8). * p<0.05 vs sham group; # p<0.05 vs I/R group.
Fig. 4.
Fig. 4.
Effect of tempol on the morphologic changes of kidney tissues. PAS staining kidney sections were taken from sham group (A), I/R group (B) and I/R pretreated with tempol (50 mg/kg, C) and kidney injury was quantitatively measured by percentage of tubular necrosis in the cortex (D). Data were expressed as mean ± SEM, n=3, * p<0.05 vs sham group, # p <0.05 vs I/R group.
Fig. 5.
Fig. 5.
Effect of tempol on the expression of Akt/mTOR and GSK3β pathways in I/R injury. Data were expressed as mean ± SEM, n=5, * p <0.05 vs sham group; # p <0.05 vs I/R group.
Fig. 6.
Fig. 6.
Effect of tempol on the expression of apoptosis and inflammation pathways in renal I/R injury. Data were expressed as mean ± SEM, n=5, * p <0.05 vs sham group; # p <0.05 vs I/R group.
Fig. 7.
Fig. 7.
Effect of tempol on the afferent arteriolar activity in renal I/R injury. A) The representative picture of microperfusion. Dose response curve for Ang II in three different groups. Arteriolar luminal diameters were given in μm (B) and contractive percent of the control diameter (C). Data were expressed as mean ± SEM, n=5, * p <0.05 vs sham group; # p <0.05 vs I/R group.
See this image and copyright information in PMC

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