Peroxisome proliferator-activated receptor-α is renoprotective in doxorubicin-induced glomerular injury

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic utilized in antitumor therapy; however, its clinical use is frequently impeded by renal toxic effects. As peroxisome proliferator-activated receptor-α (PPAR-α) has renoprotective effects in drug-related kidney injuries, we tested its ability to inhibit DOX-induced renal injury. Although both male PPAR-α knockout mice and their wild-type littermates (pure 129/SvJ background) had significant proteinuria 4 weeks after DOX treatment, those with deletion of PPAR-α had more severe proteinuria. This was associated with more serious podocyte foot process effacement compared with wild-type mice. In contrast, the PPAR-α agonist fenofibrate effectively reduced proteinuria and attenuated DOX-induced podocyte foot process effacement. Consistently, glomerular nephrin expression was significantly lower in the knockout compared with wild-type mice following DOX treatment. Fenofibrate therapy significantly blunted the reduction in glomerular nephrin levels in DOX-treated wild-type mice. In cultured podocytes, DOX induced apoptosis, increased cleaved caspase-3 levels, and decreased Bcl-2 expression, all attenuated by pretreatment with fenofibrate. Thus, PPAR-α deficiency exacerbates DOX-related renal injury, in part, due to increased podocyte apoptosis.

Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy

“…Our results reinforce the importance of mitochondria as one of the key components of this complex and a major part of the multifactorial complications of diabetes (9,10,38,39). This study underscores previous observations by our group and others that improving mitochondrial function, by targeting mitochondrial dynamics, activity, or numbers, is renoprotective in different models of kidney injury, including DN (12,(40)(41)(42)(43)(44)(45)(46)(47)(48). We provide evidence that PGC-1α is a mechanistic target of Tug1 in podocytes in the kidney, through which Tug1 regulates mitochondrial bioenergetics.…”

Nucleobindin-2 is a positive regulator for insulin-stimulated glucose transporter 4 translocation in fenofibrate treated E11 podocytes [Rapid Communication]

“…Fenofibrate was reported to protect podocytes from doxorubicin-induced injury [17] but until today there are no reports to clearly state that fenofibrate alone can differentiate podocytes. We demonstrated that fenofibrate treated E11 podocytes showed morphological change resembling those reported for the differentiation of E11 podocytes by the conventional method [12, VAMP2 interactions [13].…”

“…However, under these conditions, we are not able to perform the experiments combined with transient transfection by electroporation because the expressed protein will start to diminish 48 21]. Fenofibrate is a selective peroxisome proliferator-activated receptor-α (PPARα) agonist that is renalprotective and attenuates doxorubicin-induced podocytes foot process effacement [17]. However there are no reports studyting whether PPARα agonist affects podocytes differentiation.…”

“…Then we have to replate the electroporated cells in suitable plate and let the replated cells differentiate at 37 o C within the next 48 hours. To explore this we tested proliferatoractivated receptor-α agonist fenofibrate because previous study reported that peroxisome proliferatoractivated receptor-α is renoprotective and attenuates Doxorubicin-induced podocyte foot process effacement [17]. Also, According to FIELD study, DAIS study, and ACCORD Lipid study, fenofibrate was proved to reduce microalbuminuria in diabetic patients [18,19,20,21].…”

Overexpression of heart-type fatty acid binding protein enhances fatty acid-induced podocyte�injury

“…PPAR-α has renoprotective effects in drug-associated kidney injury. PPAR-α deficiency exacerbates doxorubicin-associated renal injury, in part through increasing podocyte apoptosis (22).…”