Acylated ghrelin protects against doxorubicin‐induced nephropathy by activating silent information regulator 1

Abstract

This study investigated the nephroprotective role of acylated ghrelin (AG) against DOX‐induced nephropathy and examined whether the protection involves silent information regulator 1 (SIRT1). Rats were divided into control, control + AG, DOX, DOX + AG, DOX + AG + [D‐Lys3]‐GHRP‐6 (a ghrelin receptor antagonist), and DOX + AG + EX‐527 (a sirt1 inhibitor). DOX was given over the first 2 weeks. AG (10 ng/kg) and both inhibitors were given as 3 doses/wk for 5 weeks. AG improved the structure and the function of the kidneys; down‐regulated the renal expression of TGF‐β1, collagen 1A1 and α‐SMA; and inhibited the renal collagen deposition in the kidneys of DOX‐treated rats. Concomitantly, it reduced the renal levels of ROS, MDA, TNF‐α, and IL‐6 and protein levels of cytochrome‐c, TGF‐β1, Smad3 and α‐SMA in these rats. In both the control and DOX‐treated rats, AG significantly increased the renal levels of SOD and GSH, decreased the expression of cleaved caspase‐3 and Bax, increased the total levels and the nuclear activity of SIRT1 and reduced the deacetylation of p53, NF‐κB and FOXO‐31. All the effects were abolished by the concurrent administration of EX‐527 and [D‐Lys3]‐GHRP‐6. In conclusion, AG prevents DOX‐induced nephropathy in SIRT1 and GSHRa1‐dependent mechanism.

Cognitive Impairment in Multiple Sclerosis

“…In the α-helix H3 recognition region, fourteen protein-DNA contacts modulate the gene expression of targets [319]. A number of factors control DNA and forkhead interactions that involve FoxO protein phosphorylation or acetylation, FoxO protein compartmentalization in the nucleus, and alteration of electrostatic changes [259,277,306,307,320,321].…”

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…SIRT1 also is closely associated with the mammalian forkhead transcription proteins [24,55,[193][194][195][196][197]. The induction of autophagy relies upon mammalian FOXO proteins of the O class that have an important relationship to neurodegenerative disorders [40,162,187,198,199].…”

“…In regard to SIRT1, SIRT1 activity leads to increased survival through inhibition of FoxO activity [5,14,[194][195][196]. Yet, FoxOs also can bind to the SIRT1 promoter region to alter forkhead transcription [206].…”

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…Phosphorylation or acetylation of FoxOs can change the binding of the C-terminal basic region to DNA to inhibit FoxO transcriptional activity [48,152,199,248]. FoxOs are intimately connected circadian rhythm since they are linked to SIRT1 [4,34,48,85,[248][249][250][251][252]. For example, insulin-phosphatidylinositol 3-kinase (PI3K) signaling that occurs in the liver is overseen by FoxO3 control of circadian rhythmicity through modulation of Clock.…”

“…In regard to SIRT1, blockade of the activity of FoxOs by SIRT1 can promote cell survival [19,67,[249][250][251]. However, FoxOs can attach to the SIRT1 promoter region to further change forkhead transcription [181].…”