Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

Abstract

BackgroundRenal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice.MethodsWe examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study.ResultsThrough hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway.ConclusionThe present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

FBW7 Regulates the Autophagy Signal in Mesangial Cells Induced by High Glucose

“…Collagen-1 (Col-1) is the main component of ECM, which is closely related to cell growth, differentiation, proliferation, repair of tissue injury and inflammation, sclerosis, and fibrosis. Abnormal synthesis of Col-I can increase the production of reactive oxygen species (ROS) in DN and can increase the level of oxidative stress, resulting in progressive glomerular injury [17, 18]. IL-1 β can also regulate the proliferation of mesangial cells, the production of ECM, and renal fibrosis.…”

Effects of Lobeglitazone, a Novel Thiazolidinedione, on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus over 52 Weeks

“…The prevalence of diabetes is increasing substantially worldwide, mainly due to increasing rates of obesity and insulin resistance [ 37 38 39 40 ], as well as in the increasing number of elderly people, in whom fracture is a critical factor affecting quality of life and mortality [ 2 ]. Under these circumstances, TZDs will continue to play a crucial role in diabetes management, and awareness of both the beneficial and side effects of these drugs is important in daily clinical practice [ 41 ]. In this study, treatment of lobeglitazone 0.5 mg once a day for 52 weeks showed no detrimental effect on BMD at the femur neck and total hip area compared to placebo.…”

VCE‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐ and CB2 receptor‐dependent pathways

“…PPARγ was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation, but it is now well established that PPARγ agonists are also exhibit anti‐inflammatory and anti‐fibrotic effects (Clark, ; Dantas et al ., ). In this regard, PPARγ is a regulator of connective tissue homeostasis, and different experimental approaches have shown that PPARγ ligands attenuate hepatic (Galli et al ., ), renal (Bae et al ., ) and pulmonary fibrosis (Milam et al ., ) as well as bleomycin‐induced skin fibrosis (Gonzalez et al ., ; Wei et al ., ; del Rio et al ., ; Ruzehaji et al ., ).…”