Etiology Of Diabetic Nephropathy Research Articles

Intestinal Absorption of Nanoparticles to Reduce Oxidative Stress and Vasoconstriction for Treating Diabetic Nephropathy.

The etiology of diabetic nephropathy (DN) is complex, and the incidence is increasing year by year. The patient's kidney showed oxidative stress damage, increasing active oxygen species (ROS) content, and vasoconstriction. Due to poor drug solubility and low renal accumulation, the current treatment regimens have not effectively alleviated glomerulopathy and other kidney damage caused by DN. Therefore, it is of great significance to explore new treatment strategies and drug delivery systems. Here, we constructed an oral nanodelivery system (Tel/CAN@CS-DA) that reduced oxidative stress and vasoconstriction. Deoxycholic acid (DA)-modified nanoparticles entered into intestinal epithelial cells (Caco2 cells) via the bile acid biomimetic pathway, then escaped from the lysosomes and eventually spat out the cells, increasing the oral absorption of nanoparticles. Chitosan (CS) nanoparticles could achieve renal targeting through specific binding with a renal giant protein receptor and deliver drugs to renal tubule epithelial cells (HK-2 cells). In vitro studies also proved that telmisartan (Tel) and canagliflozin (CAN) effectively removed cellular reactive oxygen species (ROS) and reduced HK-2 cell apoptosis caused by high glucose. In the in vivo model induced by streptozotocin (STZ), the results showed that the nanosystem not only elevated AMPK protein expression, inhibited angiotensin II (Ang II) protein expression to effectively reduce oxidative stress level, dilated renal blood vessels but also reduced the degree of inflammation and fibrosis. Overall, Tel/CAN@CS-DA multifunctional oral nanosystem can effectively treat DN with low toxicity, which provides a new idea for the treatment of DN.

Research progress in the pathogenesis and treatment of diabetic nephropathy

Diabetic nephropathy (DN) is one of the most common, frequent, age-related diseases, and it is also an important cause of chronic renal failure and end-stage renal diseases. It has always been one of the research hotspots. The high cost of treatment will bring a great burden to society and families. Therefore, it is very important to study the pathogenesis and treatment methods of DN. At present, many methods have been put forward for clinical diagnosis and treatment like Thiazolidinediones, renin inhibitor drug -aliskiren, tregs cells. These methods have their own advantages and disadvantages. However, the etiology of diabetic nephropathy is complicated and the course of the disease is long, and current treatments cannot achieve the expected target. Scholars also have studied many symptomatic treatment methods for different pathogenesis. However, the specific pathogenesis of DN has not yet been fully elucidated, and there is no special medicine for DN yet. This article briefly reviews the pathogenesis and treatments of DN based on the existing kinds of literature and new advances to provide some references for its clinical diagnosis and treatment.

Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.The impact of lowering lipids alone on the pathologic complications of Type 2 diabetes is unknown. Treatment with a novel antisense oligonucleotide directed against ApoC-III lowered triglycerides significantly in the leptin deficient BTBR ob/ob murine model of type 2 diabetes, but did not ameliorate hyperglycemia or improve the nephropathy.

Ferulic Acid Protects Hyperglycemia-Induced Kidney Damage by Regulating Oxidative Insult, Inflammation and Autophagy.

Oxidative insult, inflammation, apoptosis and autophagy play a pivotal role in the etiology of diabetic nephropathy, a global health concern. Ferulic acid, a phytochemical, is reported to protect against varied diseased conditions. However, the ameliorative role and mechanisms of ferulic acid in averting STZ-mediated nephrotoxicity largely remains unknown. For in vivo study, a single intraperitoneal injection of streptozotocin (50 mg kg-1 body wt.) was administered in experimental rats to induce diabetes. The diabetic rats exhibited a rise in blood glucose level as well as kidney to body weight ratio, a decrease in serum insulin level, severe kidney tissue damage and dysfunction. Elevation of intracellular ROS level, altered mitochondrial membrane potential and cellular redox balance impairment shown the participation of oxidative stress in hyperglycemia-triggered renal injury. Treatment with ferulic acid (50 mg kg-1 body wt., orally for 8 weeks), post-diabetic induction, could markedly ameliorate kidney injury, renal cell apoptosis, inflammation and defective autophagy in the kidneys. The underlying mechanism for such protection involved the modulation of AGEs, MAPKs (p38, JNK, and ERK 1/2), NF-κB mediated inflammatory pathways, mitochondria-dependent and -independent apoptosis as well as autophagy induction. In cultured NRK-52E cells, ferulic acid (at an optimum dose of 75 μM) could counter excessive ROS generation, induce autophagy and inhibit apoptotic death of cells under high glucose environment. Blockade of autophagy could significantly eradicate the protective effect of ferulic acid in high glucose-mediated cell death. Together, the study confirmed that ferulic acid, exhibiting hypoglycemic, antioxidant, anti-inflammatory, anti-apoptotic activities and role in autophagy, could circumvent oxidative stress-mediated renal cell damage.

Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism

Inflammation plays a central role in the etiology of diabetic nephropathy, a global health issue. We observed a significant reduction in the renal expression of fibroblast growth factor 1, a known mitogen and insulin sensitizer, in patients with diabetic nephropathy and in mouse models implying that fibroblast growth factor 1 possesses beneficial anti-inflammatory and renoprotective activities invivo. To test this possibility, we investigated the effects of chronic intraperitoneal administration of fibroblast growth factor 1 into both the streptozotocin-induced type 1 diabetes anddb/db type 2 diabetes models. Indeed, recombinant fibroblast growth factor 1 significantly suppressed renal inflammation (i.e., cytokines, macrophage infiltration), glomerular and tubular damage, and renal dysfunction in both type 1 and type 2 diabetes mice. Fibroblast growth factor 1 was able to correct the elevated blood glucose levels in type 2 but not in type 1 diabetic mice, suggesting that the anti-inflammatory effect of fibroblast growth factor 1 was independent of its glucose-lowering activity. The mechanistic study demonstrated that fibroblast growth factor 1-mediated inhibition of the renal inflammation invivo was accompanied by attenuation of the nuclear factor κB and c-Jun N-terminal kinase signaling pathways, further validated invitro using cultured glomerular mesangial cells and podocytes. Thus, fibroblast growth factor 1 holds great promise for developing new treatments for diabetic nephropathy through countering inflammatory signaling cascades in injured renal tissue.

Marginal structural model to evaluate the joint effect of socioeconomic exposures on the risk of developing end-stage renal disease in patients with type 1 diabetes: a longitudinal study based on data from the Swedish Childhood Diabetes Study Group

PurposeDiabetic nephropathy is a severe complication of type 1 diabetes (T1D) that may lead to renal failure and end-stage renal disease (ESRD) demanding dialysis and transplantation. The etiology of diabetic nephropathy is multifactorial and both genes and environmental and life style–related factors are involved. In this study, we investigate the effect of the socioeconomic exposures, unemployment and receiving income support, on the development of ESRD in T1D patients, using a marginal structural model (MSM) in comparison with standard logistic regression models. MethodsThe study is based on the Swedish Childhood Diabetes Register which in 1977 started to register patients developing T1D before 15 years of age. In the analyses, we include patients born between 1965 and 1979, developing diabetes between 1977 and 1994, and followed until 2013 (n = 4034). A MSM was fitted to adjust for both baseline and time-varying confounders. ResultsThe main results of the analysis indicate that being unemployed for more than 1 year and receiving income support are risk factors for the development of ESRD. Multiple exposures over time to these risk factors increase the risk associated with the disease. ConclusionsUsing a MSM is an advanced method well suited to investigate the effect of exposures on the risk of complications of a chronic disease with longitudinal data. The results show that socioeconomic disadvantage increases the risk of developing ESRD in patients with T1D.

Progressive renal decline as the major feature of diabetic nephropathy in type 1 diabetes.

Despite almost universal implementation of renoprotective therapies over the past 25 years, the risk of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not decreasing, and ESRD remains the major cause of excess morbidity and premature mortality [1]. Such a state of affairs prompts a call to action. In this review we re-evaluated the proteinuria-centric model of diabetic nephropathy and showed its deficiencies. On the basis of extensive studies that we have been conducting on the patients attending the Joslin Clinic, we propose that progressive renal decline, not abnormalities in urinary albumin excretion, should be considered as the major feature of disease processes leading to ESRD in T1D. The etiology of diabetic nephropathy should be reconsidered in light of our new findings so our perspective can be broadened regarding new therapeutic targets available for interrupting the progressive renal decline in T1D. Reduction in the loss of glomerular filtration rate, not reduction of albumin excretion rate, should become the measure for evaluating the effectiveness of new therapeutic interventions. We need new accurate methods for early diagnosis of patients at risk of progressive renal decline or, better still, for detecting in advance which patients will have rapid, moderate or minimal rate of progression to ESRD.

High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol

Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22phox and p47phox expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.

High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach.

OBJECTIVE— Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes.RESEARCH DESIGN AND METHODS— To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT.RESULTS— Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1).CONCLUSIONS— This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

OBJECTIVE—The purpose of this study was to examine whether known genetic risk factors for type 1 diabetes (HLA-DRB1, -DQA1, and -DQB1 and insulin locus) play a role in the etiology of diabetic nephropathy. RESEARCH DESIGN AND METHODS—Genetic analysis of HLA-DRB1, -DQA1, -DQB1 and the insulin gene (INS) was performed in the Genetics of Kidneys in Diabetes (GoKinD) collection of DNA (European ancestry subset), which includes case patients with type 1 diabetes and nephropathy (n = 829) and control patients with type 1 diabetes but not nephropathy (n = 904). The availability of phenotypic and genotypic data on GoKinD participants allowed a detailed analysis of the association of these genes with diabetic nephropathy. RESULTS—Diabetic probands who were homozygous for HLA-DRB1*04 were 50% less likely to have nephropathy than probands without any DRB1*04 alleles. In heterozygous carriers, a protective effect of this allele was not as clearly evident; the mode of inheritance therefore remains unclear. This association was seen in probands with both short (<28 years, P = 0.02) and long (≥28 years, P = 0.0001) duration of diabetes. A1C, a marker of sustained hyperglycemia, was increased in control probands with normoalbuminuira, despite long-duration diabetes, from 7.2 to 7.3 to 7.7% with 0, 1, and 2 copies of the DRB1*04 allele, respectively. This result is consistent with a protective effect of DRB1*04 that may allow individuals to tolerate higher levels of hyperglycemia, as measured by A1C, without developing nephropathy. CONCLUSIONS—These data suggest that carriers of DRB1*04 are protected from some of the injurious hyperglycemic effects related to nephropathy. Interestingly, DRB1*04 appears to be both a risk allele for type 1 diabetes and a protective allele for nephropathy.

Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes

In Diabetes Mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator of nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18-36 years) and eighteen individuals without diabetes (17-35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (microg/l) and CEC (microg/l) were significantly higher in DM (55.73 +/- 29.43, 521.47 +/- 239.13, respectively) compared to controls (24.25 +/- 10.26, 262.85 +/- 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.

Resveratrol, a Polyphenolic Phytoalexin, Attenuates Diabetic Nephropathy in Rats

Diabetic nephropathy is a serious microvascular complication and one of the main causes of end-stage renal disease. Various studies have revealed that increased oxidative stress is a major pathophysiological mechanism which is involved in the etiology of diabetic nephropathy. Resveratrol, a polyphenolic phytoalexin present in red wine, is known to possess potent antioxidant properties and thus we aimed to examine its effect on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. After 4 weeks of STZ injection, rats were divided into four groups: the control rats, diabetic rats and diabetic rats treated with resveratrol (5 and 10 mg/kg, orally) respectively from week 4 up till week 6. At the termination of the experiments, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. The levels of the renal oxidative stress markers malonaldehyde and glutathione and the antioxidant enzymes superoxide dismutase and catalase were measured in kidney homogenate. STZ-injected rats showed significant increases in blood glucose, polyuria, proteinuria and a decrease in body weight compared with age-matched control rats. After 6 weeks, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance, and proteinuria along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key antioxidant enzymes. Treatment with resveratrol significantly attenuated renal dysfunction and oxidative stress in diabetic rats. The present study reinforces the important role of oxidative stress in diabetic kidney and points towards the possible antioxidative mechanism being responsible for the renoprotective action of resveratrol.

Diltiazem Attenuates Oxidative Stress in Diabetic Rats

Diabetic nephropathy is the main cause of end stage renal damage. Oxidative stress is involved in the etiology of diabetic nephropathy and intracellular calcium is reported to play a considerable role in the development of renal damage in the diabetic kidney. Calcium antagonism can slow the progression of renal impairment in diabetes. The present study was thus designed to examine the effect of a nondihydropyridine calcium channel blocker, diltiazem, on renal function, oxidative stress, and nitric oxide (NO) release in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. After 4 weeks of STZ injection, the rats were divided in to four groups: control rats, diabetic rats treated with saline, and two groups of diabetic rats treated with diltiazem (5 and 10 mg/kg, i.p, respectively) for 8 weeks starting from 4 weeks after STZ injection. Renal function was assessed by creatinine, blood urea nitrogen, creatinine clearance, and urea clearance. Oxidative stress was measured by renal malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase. We also measured renal nitrite levels. At the end of the 8 weeks, diabetic rats exhibited renal dysfunction as evidenced by reduced creatinine and urea clearance along with enhanced albumin excretion rate as compared with control rats. Biochemical analysis of kidneys revealed a marked increase in oxidative stress demonstrated by increased lipid peroxidation and decreased activities of key antioxidant enzymes, GSH, SOD, and catalase in diabetic rats. Release of NO also significantly higher in diabetic rats than controls. Chronic treatment with diltiazem in diabetic rats significantly attenuated both renal dysfunction and oxidative stress along with increased NO levels as compared with untreated diabetic rats. The kidneys of diabetic rats showed morphological changes such as hyaline casts, glomerular thickening, and moderate interstitial fibrosis and arteriolopathy, whereas diltiazem administration markedly prevented diabetic-induced renal morphological alterations. The present study suggests that oxidative stress/nitrosative stress is increased in the diabetic kidney and calcium channel blockage can prevent these changes. The results also suggest that in STZ-induced diabetic rats, the protective action of diltiazem might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.

Elevation of resting and exercise blood pressures in subjects with type I diabetes and relation to albuminuria

The etiology of diabetic nephropathy is currently unknown, but blood pressure is believed an important risk factor. A total of 173 subjects with type I diabetes who participated in two or more exercise tests with simultaneous measurements of blood pressure (BP) and heart rate were studied. Subjects with diabetes had significantly elevated resting and exercise diastolic and systolic BPs when compared with controls. This was not related to the presence of albuminuria. During exercise, elevation of diastolic BP was present in 65 (38%) of the 173 test subjects. Elevated exercise diastolic BPs among the subjects with diabetes (excluding controls) was present only for subjects with elevated exercise and overnight albuminuria. It is concluded that factors other than early diabetic nephropathy are likely related to elevated resting and exercise BPs in subjects with diabetes compared with controls. Early renal damage, however, is related to further elevations in resting and exercise diastolic BPs within the group of subjects with diabetes.