Co-regulation of Gremlin and Notch signalling in diabetic nephropathy

Walsh, David; Roxburgh, Sarah A.; McGettigan, Paul A.; Berthier, Céline C.; Higgins, Desmond G.; Kretzler, Matthias; Cohen, Clemens D.; Mezzano, Sergio; Brazil, Derek P.; Martin, Finian

doi:10.1016/j.bbadis.2007.09.005

Cited by 105 publications

(104 citation statements)

References 55 publications

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“…Such postnatal repair has been proposed to involve the re-expression of genes previously critical to the development of the normal kidney. Indeed, the re-expression of developmental genes in response to renal damage has been reported in a number of human diseases and animal models, including ischaemia-reperfusion injury and diabetes [10,11]. However, the re-expression of Six2 in response to tubular injury, which might signal the reactivation of the embryonic nephron induction pathway, is not observed [12].…”

Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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“…A total of 320 candidate genes for diabetic nephropathy (DN) were initially selected for this study. This gene list comprised genes previously identified as differentially expressed in cell models of DN and renal biopsies (n = 210), [23][24][25][26] genes in which DNA polymorphisms have been reported to be positively associated with DN in type 1 or type 2 diabetes in at least two separate reports (n = 35), two genes previously investigated in DNA methylation studies in DN (P16) and end-stage renal disease (P66SHC), 27,28 and a subset of genes in Notch, Wnt and TGFβ developmental pathways that are implicated in DN (n = 73) (Suppl. Table 2).…”

Section: Conflict Of Interestmentioning

confidence: 99%

Comparative analysis of DNA methylation profiles in peripheral blood leukocytes versus lymphoblastoid cell lines

Brennan¹,

Ehrich²,

Brazil

et al. 2009

Epigenetics

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Previous reports have shown that DNA methylation profiles within primary human malignant tissues are altered when these cells are transformed into cancer cell lines. However, it is unclear if similar differences in DNA methylation profiles exist between DNA derived from peripheral blood leukocytes (PBLs) and corresponding Epstein-Barr Virus transformed lymphoblastoid cell lines (LCLs). To assess the utility of LCLs as a resource for methylation studies we have compared DNA methylation profiles in promoter and 5' regions of 318 genes in PBL and LCL sample pairs from patients with type 1 diabetes with or without nephropathy. We identified a total of 27 (~8%) genes that revealed different DNA methylation profiles in PBL compared with LCL-derived DNA samples. In conclusion, although the profiles for most promoter regions were similar between PBL-LCL pairs, our results indicate that LCL-derived DNA may not be suitable for DNA methylation studies at least in diabetic nephropathy.

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“…Relevant to this finding, several groups have identified increased Gremlin1 levels in a range of cancers, including colon, pituitary, malignant mesothelioma, cervical and pancreas cancers [16,17]. Importantly, levels of Gremlin1 have been shown to be elevated in human biopsies from patients with DN [11], pulmonary arterial hypertension (PAH) [10], non-ischaemic heart failure [18] and liver fibrosis [19]. In this issue of J Mol Med, Staloch and colleagues have identified a new role for Gremlin1 as a novel biomarker and potential therapeutic target in CP [20].…”

mentioning

confidence: 99%

“…Gremlin1 is involved in physiological processes such as limb and digit formation and nephrogenesis [9]. Increased Gremlin1 expression has been identified in fibrosis associated with kidney, lung, heart and liver disease [10,11]. Targeting Gremlin1 by gene deletion or shRNA knockdown reduced the severity of kidney disease in mouse models of diabetic nephropathy (DN) [12,13].…”

mentioning

confidence: 99%

Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

Brazil

2015

J Mol Med

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Chronic pancreatitis (CP) is a progressive inflammatory condition triggered by the loss of exocrine pancreatic acini and fibrosis or scarring of pancreas tissue [1]. The exocrine pancreas comprises about 90 % of total pancreas and releases digestive enzymes such as chymotrypsin, amylase and lipase in response to a meal. CP develops in 16 % of patients presenting with acute pancreatitis, a number which increases to 38 % upon second admission. The most common symptom of CP is abdominal pain, which can be both intermittent and persistent. Furthermore, 95 % of CP patients present with alcoholic or idiopathic disease [1]; however, excessive consumption of alcohol alone may not be the cause of CP. Additional causes of CP include gallstones, exposure to volatile hydrocarbons, viral infection and genetic mutations [2]. There are various genetic forms of CP including gain-of-function mutations in genes such as Prss1 which results in a form of trypsin that is resistant to degradation and can lead to an autosomal-dominant hereditary form of CP [1]. In contrast, loss-of-function mutations in genes such as Spink1 and Cftr, which is involved in the inactivation of pancreatic trypsin, are also associated with CP. The overall survival rate for CP patients is only 50 % at 20-25 years from diagnosis [3], and CP patients also have an increased risk of developing pancreatic cancer [4].Current treatments for CP involve pain management with paracetamol and non-steroid anti-inflammatory drugs as first line, followed by mild opioids such as tramadol. An important clinical feature of CP is steatorrhea, caused by reduced absorption of fat in the intestine. Supplementation of pancreatic enzymes such as lipase, together with H 2 histamine antagonists, is used to reduce this malabsorption of lipids [1]. Micronutrient therapy containing antioxidants such as Antox® (containing methyl and thiol moieties, as well as methionine and vitamin C) is now being tested, as it has been shown to control the pain and attacks associated with CP [1].

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Co-regulation of Gremlin and Notch signalling in diabetic nephropathy

Cited by 105 publications

References 55 publications

Stem cell options for kidney disease

Stem cell options for kidney disease

Comparative analysis of DNA methylation profiles in peripheral blood leukocytes versus lymphoblastoid cell lines

Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

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