Hsp90 Relieves Heat Stress-Induced Damage in Mouse Kidneys: Involvement of Antiapoptotic PKM2-AKT and Autophagic HIF-1α Signaling

Abstract

Heat stress can particularly affect the kidney because of its high rate of adenosine triphosphate consumption. Competition between apoptosis and autophagy-mediated survival always exists in damaged tissue. And Hsp90 can enhance cellular protection to resist heat stress. However, the relationship between Hsp90 and the above competition and its underlying mechanism in the kidney are unclear. The present study found that heat stress induced obvious histopathological and oxidative injury, which was connected with cellular apoptosis and autophagy in the kidney and was associated with the levels of Hsp90 expression or function. The data showed that during heat stress, Hsp90 activated the PKM2-Akt signaling pathway to exert antiapoptotic effects and induce Hsp70 expression regulated by HSF-1, stimulated autophagy-mediated survival through the HIF-1α-BNIP3/BNIP3L pathway, and finally protected the kidney from heat-stress injury. Moreover, the nuclear translocation of PKM2, (p-) Akt, HSF-1, and HIF-1α was enhanced by heat stress, but only intranuclear p-Akt and HSF-1 were specifically influenced by Hsp90, contributing to regulate the cellular ability of resisting heat-stress damage. Our study provided new insights regarding the molecular mechanism of Hsp90 in the kidney in response to heat-stress injury, possibly contributing to finding new targets for the pharmacological regulation of human or animal acute kidney injury from heat stress in future research.Autophagy, a lysosomal degradation pathway, is an essential cellular adaptation mechanism for avoiding oxidative damage. Studies of the role of autophagy in AKI have reported both beneficial and detrimental effects [12][13][14]. Light chain 3 (LC3), is essential for autophagy and serves as a vital component in monitoring autophagy and visualizing autophagosomes in vivo [15]. Pyruvate kinase M2 isoform (PKM2), a rate-limiting terminal glycolytic enzyme, catalyzes the last step of glycolysis, and recent studies have reported that PKM2 is associated with the Akt signal pathway, which regulates cell survival and apoptosis [16,17]. Meanwhile, many cellular signals have been reported to be involved in the regulation of autophagy, including the Akt (protein kinase B)-mTOR (mammalian target of rapamycin) pathway [18,19]. Furthermore, Akt also plays a vital role in resisting heat stress-induced apoptosis [20]. Hypoxia-inducible factor (HIF), especially HIF-1α, is also a major actor in the cell survival autophagy in response to hypoxia stress via BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) and BNIP3L (Bcl-2/adenovirus E1B 19-kDa interacting protein 3 like) [21]. However, understanding the roles and their interplay of autophagy and apoptosis, and identification of the closely related signaling pathways in the kidney, is still very deficient but important for controlling tissue damage during heat stress.At the cellular level, tolerance to heat stress is mainly regulated by heat shock proteins (HSPs), which are also synthesized under various environmental and oxidative...

Analysis of CircRNA Expression in Peripheral Blood of Holstein Cows in Response to Heat Stress

“…Among them, the expression of ciRNA1282 (HIF1A) was significantly changed in Sum1 compared with Spr2, and it binds to multiple miRNAs. Chen et al [ 44 ] found that Hsp90 relieves heat-stress-induced damage by involvement of autophagic HIF-1α signaling, which suggested that HIF1A might alleviate the damage caused by heat stress in animals. Moreover, ciRNA1282 (HIF1A) might bind to the bta-let-7 family, in which Bta-let-7c has been shown to promote adipocyte proliferation and inhibit adipocyte differentiation by acting as a sponge for circFUT10 [ 45 ].…”

LncRNA OIP5-AS1 reduces renal epithelial cell apoptosis in cisplatin-induced AKI by regulating the miR-144-5p/PKM2 axis

“…Increasing evidence has demonstrated that PKM2 acts as an anti-apoptotic factor against the AKT signaling pathway, which controls the cell survival and apoptosis [ 50 ]. It was reported that PKM2 could efficiently attenuate heat stress-induced damage in mouse kidneys through regulating the AKT and HIF-1α signaling pathway [ 51 ]. Knockdown of PKM2 can induce autophagic cell death in prostate cancer cells through affecting the AKT/mTOR signaling pathway [ 52 ].…”

Molecular Challenges and Opportunities in Climate Change-Induced Kidney Diseases

“…Interestingly, PKM2-Akt signaling is also known to activate HSP70. This evidence suggests that HSP90 mainly favors tubular cell survival by the inhibition of key apoptotic mediators and by the induction of autophagy and denotes a new insight of cross-talk between different HSPs [ 124 ].…”