Glucocorticoid treatment independently affects expansion and transdifferentiation of porcine neonatal pancreas cell clusters

Kim, Ji Won; Sun, Chenglin; Jeon, Sung Yoon; You, Young Hye; Shin, Ju Young; Lee, Seung‐Hwan; Cho, Jae Hyoung; Park, Chung Gyu; Yoon, Kun Ho

doi:10.5483/bmbrep.2012.45.1.51

Cited by 9 publications

(10 citation statements)

References 23 publications

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“…We suggest that PGC-1α plays a similar role in the GR-mediated repression of Pdx1 in β-cells. In line with this, a recent article showed that GCs treatment decreased Pdx1, increased PGC-1α expression, and inhibited porcine neonatal pancreas cell cluster differentiation into β-cells (41). Thus, similarly to what we show in murine fetal pancreas, PGC-1α is stimulated by GCs in porcine cells.…”

Section: Discussionmentioning

confidence: 63%

Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction

et al. 2013

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Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression.

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Section: Discussionmentioning

confidence: 63%

Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction

et al. 2013

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“…UCP-2 is expressed under conditions driving mitochondrial dysfunction, including hyperglycemia, and reduces the mitochondrial membrane potential when the electron flow cannot be coupled to ATP synthesis. PGC-1α overexpression may also inhibit β-cell differentiation [49,50]. However, human genetic studies suggest a protective role of PGC-1α in DM [51].…”

Section: Diabetesmentioning

confidence: 99%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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“…Recent studies in rodents have demonstrated that Dx suppresses the expansion and differentiation of transplanted NPCCs (18). This impairment of A-cell differentiation seemed to be mediated by pancreatic transcription factors, which might be related to the expression of PGC-1> upon Dx treatment (24). In vivo experiments clearly indicated that the expression of insulin in the graft tissue disappeared in the Dx-injected group, but the siPGC-1>-and Dx-treated group showed strong insulin expression in the graft.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, reported studies using a glucocorticoid receptorinactivation model suggested that an excess of glucocorticoid impairs the differentiation of the A-cell lineage exclusively in the pancreas (21Y23). We previously reported that Dx treatment remarkably suppressed graft mass expansion at an early stage after transplantation, and the endocrine differentiation of porcine NPCCs was correlated with the duration of Dx treatment (24). This impairment of A-cell differentiation seemed to be mediated by pancreatic transcription factors, which may play a role in the expression of PGC-1> after treatment with Dx.…”

mentioning

confidence: 97%