Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and renal tubular cell dysfunction contributes to the pathogenesis of DN. Soluble epoxide hydrolase (sEH) is an enzyme that can hydrolyze epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs) into the less biologically active metabolites. Inhibition of sEH has multiple beneficial effects on renal function, however, the exact role of sEH in hyperglycemiainduced dysfunction of tubular cells is still not fully elucidated. In the present study, we showed that human proximal tubular epithelial (HK-2) cells revealed an upregulation of sEH expression accompanied by the impairment of autophagic flux, mitochondrial dysfunction, ubiquitinated protein accumulation and enhanced endoplasmic reticulum (ER) stress after high glucose (HG) treatment. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which resulted in excessive reactive oxygen species (ROS) generation, Bax translocation, cytochrome c release, and apoptosis. However, t-AUCB, an inhibitor of sEH, partially reversed these negative outcomes. Moreover, we also observed increased sEH expression, impaired autophagy flux, mitochondrial dysfunction and enhanced ER stress in the renal proximal tubular cells of db/db diabetic mice. Notably, inhibition of sEH by treatment with t-AUCB attenuated renal injury and partially restored autophagic flux, improved mitochondrial function, and reduced ROS generation and ER stress in the kidneys of db/db mice. Taken together, these results suggest that inhibition of sEH by t-AUCB plays a protective role in hyperglycemia-induced proximal tubular injury and that the potential mechanism of t-AUCBmediated protective autophagy is involved in modulating mitochondrial function and ER stress. Thus, we provide new evidence linking sEH to the autophagic response during proximal tubular injury in the pathogenesis of DN and suggest that inhibition of sEH can be considered a potential therapeutic strategy for the amelioration of DN.

Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease

“…For instance, Luo et al demonstrated in rat models of DKD that hyperglycemia decreases EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DKD (Luo et al, 2009[ 25 ]). Moreover, an enhanced sEH expression (resulting in low levels of EETs) in murine kidneys under streptozotocin-induced diabetes (Chen et al, 2012[ 3 ]; Bettaieb et al, 2017[ 2 ]; Jiang et al, 2020[ 23 ]) and in cells exposed to hyperglycemia (Jiang et al, 2020[ 23 ]) has been repeatedly observed. Indeed, an elevation of EETs levels by inhibition of sEH have been suggested as a potential therapeutic strategy for the amelioration of DKD (Chen et al, 2012[ 3 ], Jiang et al, 2020[ 23 ]).…”

“…Moreover, an enhanced sEH expression (resulting in low levels of EETs) in murine kidneys under streptozotocin-induced diabetes (Chen et al, 2012[ 3 ]; Bettaieb et al, 2017[ 2 ]; Jiang et al, 2020[ 23 ]) and in cells exposed to hyperglycemia (Jiang et al, 2020[ 23 ]) has been repeatedly observed. Indeed, an elevation of EETs levels by inhibition of sEH have been suggested as a potential therapeutic strategy for the amelioration of DKD (Chen et al, 2012[ 3 ], Jiang et al, 2020[ 23 ]). According to these preclinical data, an sEH inhibition leads to higher concentrations of EETs which, in turn, attenuate renal tubular mitochondrial dysfunction and endoplasmic reticulum stress by restoring autophagic flux, as well as decreasing renal tubular apoptosis (Chen et al, 2012[ 3 ]; Jiang et al, 2020[ 23 ]).…”

“…Indeed, an elevation of EETs levels by inhibition of sEH have been suggested as a potential therapeutic strategy for the amelioration of DKD (Chen et al, 2012[ 3 ], Jiang et al, 2020[ 23 ]). According to these preclinical data, an sEH inhibition leads to higher concentrations of EETs which, in turn, attenuate renal tubular mitochondrial dysfunction and endoplasmic reticulum stress by restoring autophagic flux, as well as decreasing renal tubular apoptosis (Chen et al, 2012[ 3 ]; Jiang et al, 2020[ 23 ]). Our findings confirm, for the first time in humans, the importance of these eicosanoids in DKD.…”

“…Previous reports have shown that, while EETs may prevent hyperglycemia-induced damage in the kidney (Hoff et al, 2019[ 18 ]; Jiang et al, 2020[ 23 ]), 20-HETE seems to have detrimental effects (Eid et al, 2009[ 7 ], 2013[ 8 ][ 9 ]; Luo et al, 2009[ 25 ]; Ding et al, 2019[ 5 ]). However, to date, these studies have all been carried out in vitro or in animal models and there are no clinical studies that can help understand the real involvement of these AA metabolites in DKD.…”

Inhibition of the Soluble Epoxide Hydrolase as an Analgesic Strategy: A Review of Preclinical Evidence

“…Numerous studies showed sEH is a physiological modulator of ER stress signaling involved in many disorders. [105][106][107] Thus, the sEH enzyme is a nonchannel, non-neurotransmitter therapeutic and well characterized target for pain. 108 Both pain and ER stress markers are elevated in peripheral nervous system of type I diabetic rats.…”