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The genetics of diabetic nephropathy.

Brennan E, McEvoy C, Sadlier D, Godson C, Martin F - Genes (Basel) (2013)

Bottom Line: There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive.Recently, genome-wide association studies have discovered several novel genetic variants associated with DN.Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland. eoin.brennan@ucd.ie.

ABSTRACT
Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

No MeSH data available.


Related in: MedlinePlus

The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia, inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways implicated in DN may act to suppress or drive DN progression.
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genes-04-00596-f001: The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia, inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways implicated in DN may act to suppress or drive DN progression.

Mentions: During the development and progression of DN, chronic elevated blood glucose (hyperglycaemia) together with glomerular hypertension leads to renal inflammation, progressive glomerulosclerosis and tubulointerstitial fibrosis resulting in organ failure (Figure 1). High glucose, advanced glycation end-products (AGEs), Angiotensin II, and profibrotic growth factors including transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) act on multiple cell types within the kidney to effect mesangial cell matrix expansion, podocyte cell loss, tubule epithelial cell apoptosis and dedifferentiation, macrophage recruitment and fibroblast activation [22,23,24,25,26,27,28]. Among the key modulators implicated in the pathogenesis of DN are oxidative stress, protein kinase C, activation of receptor of AGEs (RAGE) and the nuclear factor-κB (NF-κB) transcription factor family (Figure 1) [29,30,31,32]. As a result of the diverse functional roles of these resident renal cell populations, it is essential that the variations in gene expression patterns within these cell populations is completely understood in the context of the pathogenesis of DN. Furthermore, epigenetic mechanisms of gene regulation, including DNA methylation, histone modifications and micro-RNA (miRNA) are now being explored in DN [33].


The genetics of diabetic nephropathy.

Brennan E, McEvoy C, Sadlier D, Godson C, Martin F - Genes (Basel) (2013)

The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia, inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways implicated in DN may act to suppress or drive DN progression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927570&req=5

genes-04-00596-f001: The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia, inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways implicated in DN may act to suppress or drive DN progression.
Mentions: During the development and progression of DN, chronic elevated blood glucose (hyperglycaemia) together with glomerular hypertension leads to renal inflammation, progressive glomerulosclerosis and tubulointerstitial fibrosis resulting in organ failure (Figure 1). High glucose, advanced glycation end-products (AGEs), Angiotensin II, and profibrotic growth factors including transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) act on multiple cell types within the kidney to effect mesangial cell matrix expansion, podocyte cell loss, tubule epithelial cell apoptosis and dedifferentiation, macrophage recruitment and fibroblast activation [22,23,24,25,26,27,28]. Among the key modulators implicated in the pathogenesis of DN are oxidative stress, protein kinase C, activation of receptor of AGEs (RAGE) and the nuclear factor-κB (NF-κB) transcription factor family (Figure 1) [29,30,31,32]. As a result of the diverse functional roles of these resident renal cell populations, it is essential that the variations in gene expression patterns within these cell populations is completely understood in the context of the pathogenesis of DN. Furthermore, epigenetic mechanisms of gene regulation, including DNA methylation, histone modifications and micro-RNA (miRNA) are now being explored in DN [33].

Bottom Line: There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive.Recently, genome-wide association studies have discovered several novel genetic variants associated with DN.Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland. eoin.brennan@ucd.ie.

ABSTRACT
Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

No MeSH data available.


Related in: MedlinePlus