Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice

Santana, Alexandre Chagas; Degaspari, Sabrina; Catanozi, Sérgio; Dellê, Humberto; Lima, Larissa de Sá; Silva, Cleonice; Blanco, Paula; Solez, Kim; Scavone, Cristóforo; Noronha, Irene L.

doi:10.1093/ndt/gfs569

Cited by 64 publications

(78 citation statements)

References 33 publications

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“…Histology shows tubulointerstitial damage with inflammatory cell infiltration, interstitial fibrosis and loss of tubular epithelial cells. No alterations of glomerular architecture are observed with this model [22]. In some, but not all published studies, proteinuria was also seen in C57BL/6 mice after adenine treatment [21,23].…”

Section: Non-surgical Modelsmentioning

confidence: 90%

“…To circumvent the problem that mice avoid eating adenine, the compound was mixed with a casein-containing diet that blunted the smell and taste [21]. Supplementation of 0.2% adenine with food for 6 weeks resulted in CKD in C57BL/6 mice with increased levels of urea, creatinine, phosphate and parathormone in serum [22]. Histology shows tubulointerstitial damage with inflammatory cell infiltration, interstitial fibrosis and loss of tubular epithelial cells.…”

Section: Non-surgical Modelsmentioning

confidence: 99%

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Non-Transgenic Mouse Models of Kidney Disease

Rabe¹,

Schaefer²

2016

Nephron

1,377

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Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches. Recently, interventional models suitable to induce acute and chronic kidney disease in the mouse have become a focus of interest due to the wide availability of genetically engineered mouse lines. These models differ by their damaging mechanism (cell toxicity, immune mechanisms, surgical renal mass reduction, ischemia, hypertension, ureter obstruction etc.), functional and histomorphological phenotype and disease evolution. The susceptibility to a damaging mechanism often depends on strain and gender. The C57BL/6 strain, the most commonly used genetic background of transgenic mice, appears to be relatively resistant against developing glomerulosclerosis, proteinuria and hypertension. This review serves to provide a comprehensive overview of interventional mouse models of acute and chronic kidney disease.

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Section: Non-surgical Modelsmentioning

confidence: 90%

Section: Non-surgical Modelsmentioning

confidence: 99%

Non-Transgenic Mouse Models of Kidney Disease

Rabe¹,

Schaefer²

2016

Nephron

1,377

View full text Add to dashboard Cite

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“…Seven-week-old wild-type C57BL/6J male mice were fed either a normal CE-2 diet (CLEA Japan, Tokyo, Japan) or a 0.2% adenine-containing CE-2 diet (CLEA Japan) for 6 weeks ad libitum (5,41). Blood lactate and serum creatinine levels were then measured at 0, 3, and 6 weeks after the start of each diet.…”

Section: Methodsmentioning

confidence: 99%

Targeting Oxygen-Sensing Prolyl Hydroxylase for Metformin-Associated Lactic Acidosis Treatment

Oyaizu-Toramaru

Suhara

Hayakawa

et al. 2017

Molecular and Cellular Biology

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Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxiainducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.KEYWORDS CKD, Cori cycle, HIF, MALA, PHD, gluconeogenesis, hypoxia, lactic acidosis, metformin, prolyl hydroxylase T he hypoxic response is mainly regulated by the heterodimeric transcription factor hypoxia-inducible factor (HIF) composed of a stable ␤-subunit (HIF␤/ARNT) and labile ␣-subunit (HIF␣). The protein expression level of HIF␣ is negatively regulated by prolyl hydroxylase PHD1 to PHD3 (prolyl hydroxylase domain-containing proteins 1 to 3). Under normoxic conditions where oxygen is available, PHDs hydroxylate proline residues on HIF␣ targeted for von Hippel-Lindau (VHL) E3 ubiquitin ligase-dependent proteasomal degradation. On the other hand, enzymatic activities of PHDs are inhibited under the hypoxic conditions where available oxygen becomes limited as PHDs are 2-oxoglutarate-dependent dioxygenases which require molecular oxygen for their enzymatic activities. Thus, HIF␣ escapes from prolyl hydroxylation-dependent protein degradation, accumulates, binds to HIF␤/ARNT, and activates transcription of hypoxic mRNA, including that of Epo (erythropoietin [EPO] gene) or Vegf (vascular endothelial growth factor gene) under hypoxia (1). We previously reported that liver-specific inactivation of Phd2, the gene for the dominant prolyl hydroxylase for HIF␣, improved the survival rate of mice with lactic acidosis by activating hepatic gluconeogenesis from circulating lactate, which contributed to reducing the blood lactate level (2).

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“…Serum and placental levels of IL-1b, IL-4, IL-6, IL-10, IFN-g and TNF-a were measured by ELISA using a commercial MILLIPLEX 1 MAP kit (Millipore Corporation, Billerica, MA, USA) (Santana et al, 2013).…”

Section: Serum and Placental Cytokinesmentioning

confidence: 99%