GSK‐3β inhibitor TDZD‐8 prevents reduction of aquaporin‐1 expression via activating autophagy under renal ischemia reperfusion injury

Abstract

Renal ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI).Aquaporin (AQP)-1 water channel in the kidney is critical for the maintenance of water homeostasis and the urinary concentrating ability. Increasing evidence supports an important role of autophagy in the pathogenesis of AKI induced by renal I/R.The purpose of the present study is to investigate whether activation of autophagy prevents downregulation of AQP1 protein induced by renal I/R and potential molecular mechanisms. Renal I/R induced consistently reduced protein expression of AQP1, 2, and 3, as well as sodium cotransporters Na + -K + -2Cl − cotransporter and α-Na,K-ATPase, which was associated with increased urine output and decreased creatinine clearance in rats. Renal I/R also suppressed autophagy and increased inflammatory responses in the kidney. 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-di one (TDZD-8), the glycogen synthase kinase-3β inhibitor, ameliorated renal injury under I/R, activated autophagy and markedly increased expression of AQPs and sodium transporters in the kidney, which was associated with improved urine output and creatinine clearance in rats. Hypoxia/reoxygenation (H/R) induced suppression of autophagy and downregulation of AQP1 in murine inner medullary collecting duct 3 (IMCD3) cells, which was fully prevented by TDZD-8 treatment. Inhibition of autophagy by 3-methyladenine or Atg5 gene knockdown attenuated recovery of AQP1 protein expression induced by TDZD-8 in IMCD3 cells with H/R. Interleukin-1 beta (IL-1β) decreased the abundance of AQP1 protein in IMCD3 cells. H/R induced increases in protein expression of nod-like receptor pyrin domain-containing 3 and IL-1β, which was reversed by TDZD-8. In conclusion, TDZD-8 treatment prevented 2 of 21 | LIU et aL.

WITHDRAWN: Ameliorative Effects of Selenium on Kidney Injury via NF-kB and Aquaporin-1 Levels

“…It can be observed in pathological conditions such as edema, and it also has an important role in kidney functions that require ltration [13]. AQP levels, which decrease in number due to damage to the kidney tissue for various reasons, may cause decreases in the ltration function of the kidney [14]. Selenium (Se) is an antioxidant and anti-in ammatory trace element [15].…”

Autophagy and regulation of aquaporins in the kidneys

“…The induction of autophagy in kidney tubular cells, particularly in proximal tubular epithelial cells, has been documented in rodent models of I/R-induced AKI [3], although suppressed autophagy has also been observed [56,57]. Our recent study revealed that the induction of autophagy by TDZD-8 (a GSK-3β inhibitor) after I/R can rescue reduced AQP1 protein expression, likely by way of clearing deleterious factors (e.g., interleukin-1β) [58]. GSK-3β is known to modulate autophagy.…”

“…GSK-3β overexpression activates the mammalian target of rapamycin complex 1 and suppresses autophagy, while its inhibition with inhibitors increases autophagic flux [59]. In vitro hypoxia/reoxygenation (H/ R) induced suppression of autophagy and downregulation of AQP1 in murine IMCD 3 cells expressing endogenous AQP1, which was fully prevented by TDZD-8 [58]. Interestingly, the inhibition of autophagy by 3-methyladenine or Atg5 gene knockdown attenuated the recovery of AQP1 protein expression induced by TDZD-8 in mIMCD3 cells with H/R.…”

Unraveling the Roles of Protein Kinases in Autophagy: An Update on Small-Molecule Compounds for Targeted Therapy

“…The SB202190 (Figure C, Table , 28 ) MAPK inhibitor promotes the transfer of TFEB and TFE3 from the cytoplasm to the nucleus and subsequently enhances autophagy and lysosomal biogenesis . As a potent, selective, and ATP-competitive inhibitor of GSK-3β, SB216763 (Figure C, Table , 29 ) and TDZD-8 (Figure C, Table , 30 ) have also been shown to activate autophagy. , Importantly, modulating bidirectional protein kinases can also alter autophagy. For example, SCH772984 (Figure C, Table , 31 ) is a new ERK1/2 inhibitor that induces autophagy in pancreatic cancer cells and may block active pancreatic stellate cells from senescence .…”