Peroxisome proliferator‐activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation

Abstract

The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator‐activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ‐dependent process. In addition, the PPARγ antagonist GW9662, which can depress total‐PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d‐PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal‐clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria‐induced crystal retention. This detrimental effect was partially reversed by 15d‐PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.

In Vitro Cell Culture Models of Hyperoxaluric States: Calcium Oxalate and Renal Epithelial Cell Interactions

“…The HK-2 cell line exposed to calcium oxalate presents increased TGF-β1 production, decreased expression of epithelial and increased mesenchymal markers, and significant mesenchymal changes, migration, and invasiveness [21]. Similar results were observed in vitro in the CaOx-exposed Madin-Darby canine kidney (MDCK) cell line, supporting the evidence for EMT in kidney stone disease [20].…”

“…Epithelial-to-mesenchymal transition (EMT), which plays an important role in processes such as inflammation, cancer, and fibrosis, is phenotypical transformation of epithelial cells in which cell-cell adhesion, morphological characteristics and polarity weaken while invasiveness and cell migration increases. This process could also be induced by oxalate crystals, most likely by activation of TGF-β1 and the Notch/Snail pathway [19,20].…”

“…It is highly expressed in renal tissues including inner medullary collecting ducts, distal tubules, and the ascending limb of Henle's loop [49], where it modulates gene expression through peroxisome proliferator response element (PPRE) sites and influences transcription of target genes [50]. PPAR-γ agonists could prevent crystal formation and cause a decrease of oxidative stress caused by oxalate, in part by inhibition of TGF-β1 signaling transduction [20,27,51]. In addition, PPAR-γ agonists also bind to hepatocyte growth factor (HGF) and lead to increased HGF gene expression.…”

Rosiglitazone Suppresses Calcium Oxalate Crystal Binding and Oxalate-Induced Oxidative Stress in Renal Epithelial Cells by Promoting PPAR-γ Activation and Subsequent Regulation of TGF-β1 and HGF Expression

“…It modulates gene expression by binding to peroxisome proliferator response element (PPRE) sites and affects the transcription of downstream target genes [10]. Li et al demonstrated that the PPAR- γ agonist 15-deoxy- Δ 12,14-prostaglandin J2 (15d-PGJ2) can prevent CaOx stone formation both in vivo and in vitro [11]. However, the mechanism of PPAR- γ signaling in oxalate-induced tubular cell injury requires further investigation.…”

“…Oxalate-induced ROS production is considered to be the result of TGF- β 1 activation [17]. Recently, multiple studies have suggested that PPAR- γ agonists can exert a therapeutic effect on kidney disease by inhibiting TGF- β 1 signal transduction [11]. PPAR- γ agonists can inhibit TGF- β 1 mRNA and protein expression [7].…”