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At least 19 recordsLinked to original sources
PubMed1998

A polymorphism in the gene for the atrial natriuretic peptide and diabetic nephropathy. Diabetic Nephropathy Study Group.

BACKGROUND: Atrial natriuretic peptide is involved in blood pressure regulation via its vasodilating and natriuretic actions. Since diabetic nephropathy and hypertension are closely related, ANP is a reasonable candidate gene for diabetic nephropathy (DN). METHODS: We genotyped 410 patients with type I diabetes (without DN n = 307; with DN n = 103) and 658 patients with type II diabetes (without DN n = 464; with DN n = 194). In the patients the duration of diabetes was at least 10 years. Diabetic nephropathy was defined as urinary albumin excretion of > or = 30 mg/24 h. The HpaII polymorphism in intron 2 of the ANP gene was determined using PCR amplification followed by restriction digest. Alleles were separated on agarose gels stained with ethidium bromide. RESULTS: We compared genotype distribution and allele frequencies between patients with and without nephropathy. No significant difference was observed either in type I (allele frequency without DN H1, 0.02/H2, 0.98 vs with DN H1, 0.05/H2, 0.95; P = 0.132) or in type II diabetes (allele frequency without DN H1, 0.04/H2, 0.96 vs with DN H1, 0.05/H2, 0.95; P = 0.551). CONCLUSIONS: The polymorphism in the gene for the atrial natriuretic peptide does not seem to play a major role in the development of diabetic nephropathy in either type I or in type II diabetes.

Adult↗
PubMed2004

[Nephrotic syndrome due to metabolic disease--special reference to diabetic nephropathy].

Diabetes has become the most common single cause of end stage renal disease. Nephrotic syndrome is often manifested in the progression of diabetic nephropathy. Diabetic nephropathy has several pathways for development, such as glomerular hyperfiltration, upregulation of protein kinase C, advanced glycation end products, activation of polyol pathway, increased oxidative stress and upregulation of growth factors. Intensive control of blood pressure and the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker can protect the progression of nephropathy with nephrotic syndrome. However further studies are necessary for the clinical guidline in patients with diabetic nephropathy manifesting with nephrotic syndrome.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1996

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy. The Diabetic Nephropathy Study Group.

BACKGROUND: There is agreement that a family history of hypertension (HT), is a predictor for the risk of diabetic nephropathy (DN) in patients with type 2 diabetes, and possibly also type 1 diabetes. It follows that genes related to the risk of hypertension must also be considered candidate genes for DN. The 235T allele of the angiotensinogen gene was found to be related to primary HT. METHODS: To examine whether it is predictive for DN as well, we examined the angiotensinogen gene polymorphism in 230 healthy local controls, 423 patients with type 1 diabetes (n = 180 with DN; n = 243 without DN) and 663 patients with type 2 diabetes (n = 310 with DN; n = 353 without DN). The angiotensinogen gene M235T polymorphism was determined using PCR amplification. RESULTS: The following results were obtained (i) no significant difference of genotype distribution (type 1: MM/MT/TT (%) 27.6/57.2/15.2 vs 27.2/56.1/16.7 (P = 0.92); type 2; MM/MT/TT (%) 31.7/48.2/2/20.1 vs. 32.9/46.8/20.3 (P = 0.93) or allele frequencies (type 1: M 0.56 vs. 0.55 (P = 0.795); type 2; M 0.56 vs. 0.56 (P = 0.86)) was found, between diabetic patients with or without DN, (ii) no difference was found between normotensive and hypertensive diabetic patients. CONCLUSION: The data argue against a role of the angiotensinogen gene M235T polymorphism in the manifestation of diabetic nephropathy or hypertension in diabetic patients.

Adult↗
PubMed1995

Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group.

In patients with type 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for angiotensin I converting enzyme and the presence of diabetic nephropathy. Our objective was (i) to assess this association in a large cohort of patients with type 1 diabetes and (ii) to examine whether this finding also applies to type 2 diabetes. We examined 247 patients with type 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with type 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between type 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between type 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either type 1 or type 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest.

Adult↗
PubMed2005

Assessing genetic susceptibility to diabetic nephropathy.

Diabetic nephropathy is a serious complication of diabetes and the leading cause of end-stage renal disease. Studies indicate both environmental and genetic factors contribute to the development and progression of diabetic nephropathy. In particular, epidemiological evidence shows a familial clustering of nephropathy in siblings with diabetes, supporting an important role of genetic susceptibility in the pathogenesis of diabetic nephropathy. A common approach in genetic research is assessment of candidate gene polymorphisms using case-control analysis; a number of studies have evaluated predictable candidate genes for diabetic nephropathy. In contrast, only a few studies have used a whole genome approach, such as scanning of micro-satellite markers, in the assessment of genetic susceptibility to diabetic nephropathy. A whole genome linkage analysis using families of Pima Indians showed susceptibility loci for diabetic nephropathy on chromosome 3, 7, and 20. Another linkage analysis using discordant sib-pairs of Caucasian families with type 1 diabetes identified a critical area on chromosome 3q. However, these results have been inconclusive and further investigation is required. Recently, a genome-wide, case-control analysis identifying susceptibility genes for diabetic nephropathy was performed. As a result, a single nucleotide polymorphism in exon 23 of the solute carrier family 12 (sodium-chloride cotransporter) member 3 gene was found to be strongly associated with diabetic nephropathy. Although further assessment of this polymorphism is needed, this strategy offers great promise in the identification of genetic factors predisposing patients to diabetic nephropathy. Identification of genetic susceptibility markers may offer new hope in the diagnosis and treatment of diabetic nephropathy.

Diabetic Nephropathies↗
PubMed2000

An evidence-based review of ACE inhibitors in incipient diabetic nephropathy.

Diabetic nephropathy develops in approximately 35% of diabetics and is the leading cause of end-stage renal disease in North America. End-stage renal disease is associated with increased morbidity and mortality, and a large economic burden. Treatments that can prevent or postpone diabetic nephropathy are important therapeutic advances. Interventional studies in type I diabetes and type II diabetes have demonstrated a beneficial effect of improved glycemic control and good blood pressure control in delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors have been found to be effective in delaying the progression of diabetic nephropathy in hypertensive as well as normotensive diabetics with early and advanced nephropathy. Microalbuminuria or incipient diabetic nephropathy is the earliest clinical expression of diabetic nephropathy and identifies patients at risk of further progression. Advanced or overt nephropathy is associated with a greater risk for coronary artery disease and mortality. It is possible that interventions aimed earlier in the cascade at preventing the development of overt nephropathy may result in greater clinical benefit. There is compelling evidence of the benefit of ACE inhibitors in preventing the progression of incipient diabetic nephropathy to overt diabetic nephropathy in normotensive diabetics.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

[Care of patients with diabetic nephropathy].

Diabetic nephropathy is one of the main causes of chronic renal failure in developed countries. The genesis and development of diabetic nephropathy is associated in both types of diabetes with a more rapid progression of other secondary complications and an increased mortality, in particular cardiovascular mortality. The main causes of development of diabetic nephropathy are prolonged hyperglycaemia along with a so far not elucidated inborn disposition. The course of diabetic nephropathy is characterized more clearly in type 1 diabetes. The clinically manifest stage is already irreversible and in the course of years it develops into chronic renal failure. Preventive and curative measures include maintenance of optimal metabolic control, systematic control of blood pressure, in particular by ACE-inhibitors, and a reduction of protein intake. Systematic multidisciplinary collaboration in care for patients with diabetic nephropathy helps to prevent the progression of other secondary complications such as diabetic foot and diabetic retinopathy. At present in the Czech Republic dialysis methods substituting renal function are available to practically all patients with diabetic nephropathy. As regards survival time and quality of life the optimal method of renal function replacement for patients in the terminal stage of diabetic nephropathy is transplantation.

Diabetic Nephropathies↗
PubMed2005

Synergistic contributions of carbonyl stress and megsin in diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal failure. The primary glomerular changes in diabetic nephropathy are diffuse and nodular glomerulosclerosis, manifested by an increase in mesangial matrix. Research has demonstrated that advanced glycation end products (AGEs), oxidative stress, and carbonyl stress might play a crucial role in the pathogenesis of diabetic nephropathy via multiple mechanisms. AGEs augment extracellular matrix synthesis, contribute to the release of proinflammatory cytokines and expression of growth factors and adhesion molecules, and interact with the renin-angiotensin system. Megsin is a novel serine protease inhibitor predominantly expressed in mesanguim. Megsin is upregulated in kidney samples of patients with diabetic nephropathy. Transgenic mice overexpressing megsin spontaneously develop kidney disease characterized by mesangial injury. Megsin is likely to contribute to mesangial injury in the process of diabetic nephropathy. Lack of appropriate animal models has hampered understanding the pathogenesis of diabetic nephropathy and development of effective therapies. Megsin and AGEs are suitable targets for new drugs of diabetic nephropathy and for the development of appropriate animal models of diabetic nephropathy.

Animals↗
PubMed1989

Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.

Diabetic nephropathy develops in less than half of all patients with diabetes. To study heredity as a possible risk factor for diabetic kidney disease, we examined the concordance rates for diabetic nephropathy in two sets of families in which both probands and siblings had diabetes mellitus. In one set, the probands (n = 11) had no evidence of diabetic nephropathy, with normal creatinine clearance and a urinary albumin excretion rate below 45 mg per day. In the other set, the probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence of nephropathy was found in 2 of the 12 diabetic siblings of the probands without nephropathy (17 percent). Of the 29 diabetic siblings of probands with diabetic nephropathy, 24 (83 percent) had evidence of nephropathy (P less than 0.001), including 12 with end-stage renal disease. No significant differences were noted between the sibling groups with respect to the duration of diabetes, blood pressure, glycemic control, or glycosylated hemoglobin levels. Logistic regression analysis found nephropathy in the proband to be the only factor significantly predictive of the renal status of the diabetic sibling. We conclude that diabetic nephropathy occurs in familial clusters. This is consistent with the hypothesis that heredity helps to determine susceptibility to diabetic nephropathy. However, this study cannot rule out the possible influences of environmental factors shared by siblings.

Adolescent↗
PubMed2001

Association of transforming growth factor-beta1 T29C polymorphism with the progression of diabetic nephropathy.

Diabetes mellitus is a leading cause of end-stage renal disease in the Western world. Histologically, mesangial expansion with increased extracellular matrix protein is observed in patients with diabetic nephropathy. Because transforming growth factor (TGF)-beta promotes extracellular matrix production in response to high glucose, TGF-beta is considered to play a central role in the pathogenesis of diabetic nephropathy. We investigated the association of TGF-beta1 T29C polymorphism and the progression of diabetic nephropathy. Forty patients with type 2 diabetes mellitus were enrolled. All patients had had diabetes for more than 10 years. DNA was extracted from peripheral blood cells, and genotype was determined using real-time polymerase chain reaction method. Patients were classified into three groups according to genotype: TT, TC, and CC. Grade of diabetic nephropathy was determined using the amount of urinary excretion of albumin. Demographic characteristics of the patients with each genotype were not statistically different. No differences in the glycemic control and the mode of therapy were observed. Among patients with three genotypes, the severity of diabetic nephropathy was not statistically different. The patients with TT genotype tended to have a higher rate of progression of nephropathy; however, no statistically significant difference was observed among the three groups. Our results suggest that TGF-beta1 T29C polymorphism is not associated with the progression of diabetic nephropathy. Further studies are required to determine the exact role of this polymorphism in the progression of diabetic nephropathy.

Aged↗
PubMed1996

Genetics of diabetic nephropathy.

Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, a relentless decline in GFR, raised arterial blood pressure, and increased relative mortality for cardiovascular diseases. Diabetic nephropathy is a leading cause of end-stage renal failure. The pathogenesis of diabetic nephropathy is multifactorial, with contributions from metabolic abnormalities, hemodynamic alterations, and various growth factors and genetic factors. Epidemiologic and family studies have demonstrated that only a subset of the patients develop this complication that family clustering of nephropathy is present, and that ethnicity plays an important role in the risk of developing this kidney disease. Short stature and low birth weight are both associated with increased risk of developing diabetic nephropathy, supporting the hypothesis that genetic predisposition or factors operating in utero, in early childhood, or both contribute to the development of diabetic nephropathy. Studies elucidating phenotypic markers such as parenteral hypertension and systemic blood pressure elevation have yielded conflicting results. The contribution from elevated blood pressure only plays a minor role in the majority of the patients developing diabetic nephropathy. The majority of the studies have demonstrated increased sodium/lithium countertransport activity in insulin-dependent diabetes mellitus patients with nephropathy, whereas studies of this phenotypic marker in parents of patients with and without nephropathy have yielded conflicting results. Recently, studies of genetic markers involved in the regulation of blood pressure and levels of cardiovascular risk factors have been conducted. Several studies have demonstrated that the deletion polymorphism in the angiotensin-I-converting enzyme acts as a risk factor for cardiovascular disease in diabetic patients. However, a meta-analysis does not support the suggestion that this factor plays any role for the initiation of diabetic nephropathy. Similar negative results have been obtained in relation to polymorphisms of the genes encoding for angiotensinogen and the angiotensin II Type 1 receptor. However, studies in diabetic and non-diabetic glomerulopathies have clearly demonstrated a deleterious effect of the deletion polymorphism in the angiotensin-converting enzyme on the progression of kidney function.

Antiporters↗
PubMed2000

Pancreas transplantation for the prevention of diabetic nephropathy.

Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use of intensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy.

Albuminuria↗
PubMed2000

Ultrastructural characteristics of diabetic nephropathy.

Diabetic nephropathy is a major cause of chronic renal failure in Japan, and the prevalence rate has markedly increased during the past decade. Diabetic nephropathy shows various specific histological changes not only in glomeruli but also in the interstitial region. Nodular, diffuse, and exudative lesions, so-called diabetic glomerulosclerosis, are well known as glomerular lesions. At first, they were historically evaluated only by light microscopy, and thus which components of the glomeruli were modified was not sufficiently clear. Subsequent electron microscopic studies clarified that the expansion of the mesangial matrix was the true form of nodular and diffuse lesions, and that insudated serum substance was the real appearance of an exudative lesion. Interstitial lesions also exhibit specific features in diabetic nephropathy. In electron microscopic studies, it was proved that the size of mitochondria and thickness of the tubular basement membrane were increased in diabetic nephropathy. In this review, we introduce typical electron microscopic findings in diabetic nephropathy and recent opinions on the progression of diabetic nephropathy.

Diabetic Nephropathies↗
PubMed2006

SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). Genetic susceptibility plays an important role in the development and progression of diabetic nephropathy. Previous studies have revealed that polymorphisms in the SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) gene, which encodes solute carrier family 12 member 3, might contribute to genetic susceptibility to diabetic nephropathy and essential hypertension. In this study, we examined whether the SLC12A3 gene locus is associated with ESRD resulting from diabetic nephropathy. We genotyped 11 common single nucleotide polymorphisms (SNPs) in the SLC12A3 gene in 177 patients with ESRD due to type 2 diabetes and 184 patients with diabetic retinopathy but with no signs of renal involvement. Three SNPs (g.34372G>A [Arg913Gln], g.39143G>A, and g.41727C>T) were found to be associated with ESRD due to diabetic nephropathy. These three SNPs were in complete linkage disequilibrium. Haplotype 4 in block 2 (18806C, 21822C, 34372A, 39143A, 39240T, 39375C, and 41727T) showed a significant association with ESRD due to type 2 diabetes (P = 0.0028). These results suggest that the SLC12A3 gene locus is associated with ESRD due to diabetic nephropathy.

Adult↗
PubMed2000

Molecular mechanism of diabetic nephropathy.

Diabetic nephropathy is one of the main causes of renal end-stage disease. Morphologically, the development of diabetic nephropathy is characterized by progressive thickening of the glomerular basement membrane and by expansion of the mesangial matrix which correlates to glomerular filtration function. In vitro studies with cultured mesangial cells revealed that elevated glucose concentrations increase collagen synthesis similar to the in vivo situation. These studies showed that hyperglycemia may be toxic either by non-enzymatic reaction of glucose with proteins and subsequent formation of advanced glucosylation end products or by increased metabolism leading to increased oxidative stress and activation of protein kinase C resulting in increased production of cytokines. Particularly, de novo synthesis of transforming growth factor beta1 (TGF-beta1) is induced and TGF-beta1 appears also involved since blockage of this prosclerotic factor inhibits high glucose-induced collagen synthesis. Interestingly, it could be demonstrated that angiotensin II also stimulates TGF-beta1 production possibly via the same signal transduction pathway. Besides the classical clinical chemical parameters for evaluation of renal function, the measurement of urinary albumin excretion is now widely used for detection of developing diabetic nephropathy. Since diabetes causes glomerular and tubular changes, tubular marker proteins may be used to detect early renal damage. An increased urinary excretion of matrix proteins (e.g. collagen) and cytokines (e.g. TGF-beta1) was found in early diabetic nephropathy. However, the diagnostic value of these new parameters remains to be established.

Biomarkers↗
PubMedDate not supplied

Genetic basis of diabetic nephropathy.

Diabetes mellitus is the leading cause of end-stage renal disease. Development and progression of diabetic nephropathy result from a combination of genetic susceptibility and metabolic and hemodynamic abnormalities. In America, some racial and ethnic minorities have a significant burden of diabetic nephropathy, and, although genetic studies suggest that inherited factors play a major role in the pathogenesis of diabetic nephropathy, little information has been gained on the genes and molecular mechanisms involved. The genetic background of diabetic nephropathy is believed to be polygenic, and the genes predisposing to the development and progression of diabetic nephropathy are actively being investigated. New knowledge in identifying and understanding the role of susceptibility gene(s) will provide valuable information that could help develop new preventive and therapeutic strategies.

Albuminuria↗
PubMed2006

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (alpha-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and alpha-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.

Actins↗