Chrysin ameliorates podocyte injury and slit diaphragm protein loss via inhibition of the PERK-eIF2α-ATF-CHOP pathway in diabetic mice

Abstract

Glomerular epithelial podocytes are highly specialized cells that play a crucial role in maintaining normal function of the glomerular filtration barrier via their foot processes. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid found in propolis and mushrooms that has anti-inflammatory, antioxidant and anticancer properties. This study aimed to evaluate the renoprotective effects of chrysin on podocyte apoptotic loss and slit diaphragm protein deficiency in high glucose-exposed podocytes and in db/db mouse kidneys. Exposure to high glucose (33 mmol/L) caused glomerular podocyte apoptosis in vitro, which was dose-dependently attenuated by nontoxic chrysin (1-20 μmol/L) through reduction of DNA fragmentation. Chrysin treatment dose-dependently restored the increased Bax/Bcl-2 ratio, and suppressed Apaf-1 induction and the elevated cytochrome c release in high glucose-exposed renal podocytes. In diabetic db/db mice, oral administration of chrysin (10 mg·kg·d, for 10 weeks) significantly attenuated proteinuria, and alleviated the abnormal alterations in glomerular ultrastructure, characterized by apoptotic podocytes and foot process effacement. In addition, this compound improved the induction of slit diaphragm proteins podocin/nephrin in the diabetic glomeruli. Exposure to high glucose elevated the unfolded protein response (UPR) to ER stress in renal podocytes, evidenced by up-regulation of PERK-eIF2α-ATF4-CHOP. Chrysin treatment blocked such ER stress responses pertinent to podocyte apoptosis and reduced synthesis of slit diaphragm proteins in vitro and in vivo. These observations demonstrate that targeting ER stress is an underlying mechanism of chrysin-mediated amelioration of diabetes-associated podocyte injury and dysfunction.

Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy

“…Similarly, chrysin, a natural flavonoid, attenuates podocytes apoptosis in diabetic mice via the inhibition of the ER stress-mediated PERK-eIF2α pathway. 48 …”

The protective effects of rapamycin on cell autophagy in the renal tissues of rats with diabetic nephropathy via mTOR-S6K1-LC3II signaling pathway

“…In turn, these conditions cause irreversible podocyte injury and dysfunction, which decrease the number of podocyte [ 6 ]. Podocyte damage and loss seriously damage the integrity of the glomerular filtration barrier, leading to proteinuria and podocyte injury and promoting glomerular sclerosis, which accelerate the progression of diabetic nephropathy [ 7 ]. In our study, we found significant differences in the morphological, structural, and functional aspects of podocytes in the kidney tissues of rats with DN compared with those in the NC group.…”

Eucalyptol Inhibits Advanced Glycation End Products‐Induced Disruption of Podocyte Slit Junctions by Suppressing Rage‐Erk‐C‐Myc Signaling Pathway

“…Accordingly, eucalyptol maintained robust filtration slits and normal foot processes of podocytes. Similarly, the flavone chrysin ameliorates slit diaphragm protein loss via the inhibition of endoplasmic reticulum stress in diabetic mice . However, there is a lack of effective therapeutic drugs to maintain the podocyte integrity.…”