Preventive effect of nebivolol on contrast-induced nephropathy in rats.

BACKGROUND: Altered renal vasodilatation and oxidative stress are important mechanisms of contrast-induced nephropathy (CIN). The aim of the present study was to assess the effect of nebivolol, a beta blocker, on prevention of CIN. We hypothesized that nebivolol may prevent CIN due to its renal vasodilatation and antioxidant effects. METHODS: Thirty-two Wistar-albino rats were divided into four groups (n = 8 each): control (C), contrast media (CM), nebivolol (N), and nebivolol + contrast media (NCM). CIN was induced by administration of intravenous high-osmolar contrast media diatrizoate (6 ml/kg) after 72 h of dehydration. Nebivolol (2 mg/kg) was given internally once daily for 5 days. Kidney function parameters, nitric oxide metabolites and oxidative stress markers were measured. Kidneys were excised for pathological evaluation. RESULTS: The decrease of creatinine clearance was 0.180 +/- 0.11 mg/dl in CM, and 0.030 +/- 0.10 mg/dl in NCM (P = 0.01). Microproteinuria was ameliorated using nebivolol (P = 0.001). Serum protein carbonyl content, malonyldialdehyde and kidney thiobarbituric acid-reacting substances levels were higher in CM than in C (P = 0.003, P < 0.001 and P = 0.034, respectively) and serum thiol was lower in CM than in C (P = 0.001). However, oxidative stress markers were similar in NCM and C. Diatrizoate decreased kidney nitrite levels, but nebivolol increased them (P = 0.027). Nebivolol attenuated the tubular necrosis, proteinaceous casts and medullary congestion, although significant protective effects, were observed in tubular necrosis (P = 0.001) and proteinaceous cast (P < 0.001). CONCLUSION: This study demonstrated the protective role of nebivolol against CIN.     

The role of DJ-1/Nrf2 pathway in the pathogenesis of diabetic nephropathy in rats

Diabetic nephropathy (DN) is one of the most common chronic complications of diabetes, which is associated with an increased oxidative stress induced by hyperglycemia and alterations in DJ-1/NF-E2-related factor-2 (Nrf2) pathway. In the present study, we investigated the role and the proper time nodes of DJ-1/Nrf2 pathway in the pathogenesis of DN. Diabetes mellitus (DM) model of rats was induced by intraperitoneal injection of streptozotocin (STZ) on male Sprague–Dawley (SD) rats. Then, the diabetic rats were divided into 4, 8 and 12 weeks groups. As early at 4 weeks of diabetes, renal histologic evaluation score, cystatin C (Cys C), β2-microglobulin (β2-MG) and malondialdehyde (MDA) levels were increased, and total antioxidative capacity (T-AOC) level was decreased as compared with that in the control group. The protein expressions of DJ-1, NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) were upregulated compared with the control group from 4 weeks and further increased with the progression of DM. The protein expressions of DJ-1, Nrf2 and HO-1 in renal tissues have good line correlations with renal histologic evaluation score, respectively. Taken together, these results suggested that the activation of DJ-1/Nrf2 pathway was involved in the pathogenesis of diabetic nephropathy in rats.     

Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker of contrast-induced nephropathy after computed tomography

Contrast-induced nephropathy (CIN) is a common cause of hospital-acquired acute kidney injury (AKI) and a source of significantly increased short- and long-term mortality. Studies of large cohorts have revealed that more than half of these cases are in subjects undergoing cardiac catheterization and intra-arterial coronary angiography, and nearly a third follow computed tomography (CT) scans. Neutrophil gelatinase-associated lipocalin (NGAL) represents an early predictive troponin-like biomarker for AKI. Its role in the timely diagnosis of CIN has already been examined in adults and children undergoing coronary angiography and a meta-analysis revealed a very good performance of plasma or urine NGAL in the prediction of CIN. Much of these data have been extrapolated to patients receiving intravenous (IV) contrast agent for CT scans, although major differences in patient populations, contrast volume administered and intra-procedural complications between the two settings exist. In this context, a recent prospective study by our group evaluated plasma NGAL, measured using standardized Τriage® NGAL test (Biosite Incorporated, San Diego, CA) at baseline and 6-h post-procedure, for early detection of CIN among hospitalized patients undergoing elective contrast-enhanced CT. CIN, defined as an increase in serum creatinine (SCr) of >25% or >0.5?mg/dL from baseline within 48-h post-procedure, was found in 8.51% of subjects. In contrast, significant elevation of plasma NGAL was found at 6-h post-procedure with excellent performance characteristics. This review presents the current status of NGAL in the prediction of CIN after IV contrast administration among hospitalized patients undergoing elective contrast-enhanced CT.     

Periprocedural effects of statins on the incidence of contrast-induced acute kidney injury: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: The reports on the efficacy of statins for the prevention of contrast-induced acute kidney injury (CIAKI) remain controversial. The objective of this meta-analysis was to assess the effect of statins for the prevention of CIAKI. Methods: Comprehensive literature searches for randomized controlled trials (RCTs) of periprocedural statin treatment for prevention of CIAKI were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials Systematic Reviews and clinicaltrials.gov from inception until May 2014. The primary outcome was the incidence of CIAKI. Results: Thirteen prospective RCTs were included in our analysis. Of 5803 patients with contrast exposures, 304 patients (5.2%) had CIAKI. Patients in the statin group had an overall lower incidence of CIAKI (3.6%) compared to the control group (6.9%). Intravenous (IV) fluid hydration was used in both groups of all included studies for prevention of CIAKI. There was a significant protective effect of periprocedural statins on the incidence of CIAKI when compared to the control group [risk ratios (RRs): 0.49; 95% CI: 0.37–0.66, I² of 25%]. Conclusions: Our study demonstrates a statistically significant protective effect of statin treatment during procedures with contrast exposures. This finding suggests the use of statins in addition to standard IV crystalloid hydration may be beneficial in the prevention of CIAKI.     

Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis.

BACKGROUND: Renal fibrosis is central to the progression of diabetic nephropathy; however, the mechanisms responsible for fibroblast and matrix accumulation in this disease are only partially understood. Macrophages accumulate in diabetic kidneys, but it is unknown whether macrophages contribute to renal fibrosis. Therefore, we examined whether macrophage accumulation is associated with the progression of renal injury and fibrosis in type 1 diabetic nephropathy and whether macrophages exposed to the diabetic milieu could promote fibroblast proliferation. METHODS: Kidney macrophages, renal injury and fibrosis were analysed in diabetic C57BL/6J mice at 2, 8, 12 and 18 weeks after streptozotocin injection. Isolated rat bone marrow macrophages were stimulated with diabetic rat serum or carboxymethyllysine (CML)-bovine serum albumin (BSA) to determine whether macrophage-conditioned medium could promote the proliferation of rat renal (NRK-49F) fibroblasts. RESULTS: Progressive injury and fibrosis in diabetic nephropathy was associated with increased numbers of kidney macrophages. Macrophage accumulation in diabetic mice correlated with hyperglycaemia (blood glucose, HbA1c levels), renal injury (albuminuria, plasma creatinine), histological damage and renal fibrosis (myofibroblasts, collagen IV). Culture supernatant derived from bone marrow macrophages incubated with diabetic rat serum or CML-BSA induced proliferation of fibroblasts, which was inhibited by pre-treating fibroblasts with interleukin-1 (IL-1) receptor antagonist or the platelet-derived growth factor (PDGF) receptor kinase inhibitor, STI-571. CONCLUSION: Kidney macrophage accumulation is associated with the progression of renal injury and fibrosis in streptozotocin-induced mouse diabetic nephropathy. Elements of the diabetic milieu can stimulate macrophages to promote fibroblast proliferation via IL-1- and PDGF-dependent pathways which may enhance renal fibrosis.     

Impact of diabetic and pre-diabetic state on development of contrast-induced nephropathy in patients with chronic kidney disease.

BACKGROUND: The aim of the present study was to assess the influence of diabetic and pre-diabetic state on the development of contrast-induced nephropathy (CIN) in chronic kidney disease patients undergoing coronary angiography. METHODS: A total of 421 patients with Cockcroft clearance between 15 and 60 ml/min were divided into three groups [diabetes mellitus (DM), n = 137; pre-diabetes (pre-DM), n = 140; and normal fasting glucose (NFG), n = 144]. CIN was defined as an increase of > or =25% in creatinine over baseline within 48 h of angiography, DM as glucose > or =126 mg/dl, pre-DM as glucose between 100 and 125 mg/dl and NFG as glucose <100 mg/dl. RESULTS: CIN occurred in 20% of the DM [relative risk (RR) 3.6, P = 0.001], 11.4% of the pre-DM (RR 2.1, P = 0.314) and 5.5% of the NFG group. The decrease of glomerular filtration rate (GFR) was higher in DM and pre-DM (P = 0.001 and P = 0.002, respectively). GFR < or =30 ml/min (RR 19.22), multivessel involvement (RR 7.59), hyperuricaemia (RR 3.95), use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker (RR 2.70) and DM (RR 2.34) were predictors of CIN. Length of hospital stay was 2.45 +/- 1.45 day in DM, 2.27 +/- 0.68 day in pre-DM and 1.97 +/- 0.45 day in NFG (P < 0.001, DM vs NFG and P = 0.032, pre-DM vs NFG). The rate of major adverse cardiac events was 8.7% in DM, 5% in pre-DM and 2.1% in NFG (P = 0.042, DM vs NFG). Haemodialysis was required in 3.6% of DM and 0.7% in pre-DM (P = 0.036, DM vs NFG), and the total number of haemodialysis sessions during 3 months was higher in DM and pre-DM (P < 0.001). Serum glucose > or =124 mg/dl was the best cut-off point for prediction of CIN. CONCLUSION: Our data support that patients with DM are at a higher risk of developing CIN, but patients with pre-DM are not at as high a risk for developing CIN as diabetes patients.     

Review: Endothelial‐myofibroblast transition,a new player in diabetic renal fibrosis

Diabetic nephropathy (DN) is the most common cause of chronic kidney failure and end‐stage renal disease in the Western world. Studies from diabetic animal models and clinical trials have shown that inhibition of the renin‐angiotensin system delays the progression of advanced DN. However, a recent large‐scale clinical trial has revealed that inhibition of renin‐angiotensin system in early phases of DN does not slow the decline of renal function or the development of morphological lesions, suggesting that different mechanism(s) may be involved in the different stages of DN. The role of epithelial‐mesenchymal transition in renal fibrosis has been intensively investigated. Recently, endothelial‐mesenchymal transition, or endothelial‐myofibroblast transition (EndoMT) has emerged as another mechanism involved in both developmental and pathological processes. The essential role of EndoMT in cardiac development has been thoroughly studied. EndoMT also exists and contributes to the development and progression of cardiac fibrosis, lung fibrosis, liver fibrosis and corneal fibrosis. EndoMT is a specific form of epithelial‐mesenchymal transition. During EndoMT, endothelial cells lose endothelial markers and obtain mesenchymal markers. Recent evidence from our laboratory and others suggests that EndoMT plays an important role in the development of renal fibrosis in several pathological settings, including experimental DN. This review considers the evidence supporting the occurrence of EndoMT in normal development and in pathology, as well as the latest findings suggesting EndoMT contributes to fibrosis in DN. Whether experimental findings of EndoMT will be reproduced in human studies remains to be determined.     

Serum NGAL,cystatin C and urinary NAG measurements for early diagnosis of contrast-induced nephropathy in children

Aim: The study investigated a number of biomarkers for the early diagnosis of contrast-induced nephropathy (CIN), which is an important cause of acute kidney injury (AKI). Material and methods: The study included 91 children scheduled for elective cardiac angiography and 50 healthy controls. Biomarkers including serum (s) and urinary (u) sodium, serum and u-creatinine, s-cystatin-C, serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary N-acetyl beta glucosaminidase (u-NAG)/creatinine ratio were measured 4 times sequentially in the patients and once in the controls. Results: The patient group comprised 40 males (44%) and 51 females (56%) while the control group comprised 16 males (32%) and 34 females (68%). Age, gender, s-creatinine, estimated-glomerular filtration rate (eGFR), s-cystatin-C and fractional-excretion of sodium did not differ significantly between the groups. Serum sodium and s-NGAL were found to be lower in the patients than those of in the controls, while their u-NAG/creatinine ratio was found to be higher. Sequential data analysis revealed that s-NGAL and u-NAG/creatinine ratio increased in the first 6?h after radiocontrast media (RCM) administration and decreased at 12 and 24?h. Serum BUN and s-cystatin-C levels also showed a significant difference during the 24-h follow-up. eGFR, s-sodium and s-creatinine levels did not change in the following period. Serum cystatin-C levels revealed a significant negative correlation with eGFR. Administered RCM doses showed a positive correlation only with u-NAG/creatinine ratios. Conclusion: In the first 24?h, s-cystatin-C, s-NGAL and especially u-NAG/creatinine ratio showed promise as biomarkers, but eGFR is not adequate for early diagnosis of CIN. Sequential measurement of biomarkers may contribute to more accurate diagnosis of AKI.     

乙酰肝素酶在糖尿病肾病大鼠蛋白尿发生中的作用

目的 观察糖尿病肾病大鼠肾组织乙酰肝素酶（HPA）的表达，探讨其在糖尿病肾病大鼠蛋白尿发生中的作用。 方法 SD健康大鼠被随机分为健康对照组（n = 6）、糖尿病6周组(DM6w, n = 10)和糖尿病12周组(DM12w, n = 10)，采用一次性腹腔注射链脲菌素（STZ）的方法建立糖尿病大鼠模型。分别于造模后6周和12周末测定各组大鼠相对肾质量、血糖、尿素氮、血肌酐、24 h尿量及尿蛋白量(24 h)等指标，并观察肾脏病理改变。RT-PCR和免疫组织化学法检测各组大鼠肾组织HPA mRNA和蛋白表达变化，并分析其与蛋白尿发生的相关性。 结果 （1）DM6w和DM12w组大鼠的相对肾质量、血糖、尿素氮、24 h尿量及尿蛋白量(24 h)与健康对照组相比明显升高, 差异均有统计学意义(P < 0.05或P < 0.01)。（2）DM6w和DM12w组大鼠HPA mRNA和蛋白表达比健康对照组均显著增高(P < 0.01)。（3）大鼠肾组织HPA mRNA和蛋白表达与尿蛋白量(24 h)之间均呈正相关 (r = 0.783，P < 0.01；r = 0.793，P < 0.01)。 结论 HPA在糖尿病肾病中的表达升高可能参与了糖尿病肾病蛋白尿的发生。     

2型糖尿病肾病并发骨质疏松大鼠模型研究

目的构建2型糖尿病肾病并发骨质疏松大鼠模型。方法选用SD大鼠,通过喂养高糖高脂饲料4周后,予以链脲佐菌素(STZ 35 mg/kg)进行腹腔注射,继续喂养4周后观察血糖、尿量、尿蛋白及Ca、P等生化指标变化,通过双能X线测量骨密度以及进行生物力学检测骨强度,并取肾、骨组织进行病理检测。结果造模组在高糖高脂饲料喂养后,血糖、尿量及尿蛋白较正常组均逐渐升高,在第4周腹腔注射链脲佐菌素后,造模组的血糖、尿量及尿蛋白较正常组显著升高。在第8周时,造模组的血糖、尿量、尿蛋白及尿Ca、P均明显高于正常组,差异有统计学意义。造模组的骨密度及骨骼强度低于正常组。病理显示造模组大鼠出现肾脏肥大,肾小球毛细血管袢肥大,系膜基质增多肾脏病变以及骨小梁稀疏、变细、连续性中断等骨骼病变。结论通过腹腔注射链脲佐菌素联合8周高糖高脂饮食可建立2型糖尿病肾病并发骨质疏松的大鼠模型,该模型具有高糖、多尿、尿蛋白增加、骨密度下降以及肾小球病变和骨吸收增加的特点。     

Uric acid as a mediator of diabetic nephropathy

Despite advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end-stage renal disease in the United States and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the past decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to decrease uric acid levels and assess the impact of such therapy on diabetic kidney disease.     

The role of theophylline in contrast-induced nephropathy: a case-control study.

BACKGROUND: Various strategies for the prevention of contrast-induced nephropathy (CN) have been studied, with conflicting results. Adenosine may play an important role in the pathogenesis of CN. This study prospectively assessed the role of oral theophylline in the prevention of CN. METHODS: We randomized into two groups 70 patients with diabetes mellitus who were undergoing coronary angiography (CAG) with high-osmolar contrast media. Group I (n=35) underwent routine CAG, and group II (n=35) received oral theophylline 200 mg b.d. 24 h before and for 48 h after CAG. Serum Na(+), K(+), blood urea nitrogen (BUN), creatinine, osmolality, glomerular filtration rate (GFR) and urinalysis were performed before and after CAG. The (99m)Tc-DTPA-clearance method was used to assess GFR. RESULTS: Following angiography, patients in the control group showed a significant rise in serum creatinine (1.19+/-0.23 vs 1.44+/-0.32 mg/dl, P=0.003) and BUN (13.95+/-2.61 vs 17.55+/-3.9 mg/dl, P=0.01) along with a fall in GFR (85.4+/-14.7 vs 66.85+/-14.8 ml/min, P=0.008). The mean percentage fall in GFR was 35.8%. There was no significant change in serum creatinine (1.16+/-0.18 vs 1.24+/-0.21 mg/dl), BUN (12.8+/-3.36 vs 14.8+/-2.5 mg/dl) and GFR (86.8+/-15.8 vs 80.3+/-16.0 ml/min) in those receiving theophylline. No patient in the theophylline group had a >25% rise in serum creatinine, compared with 7/35 in the control group (P=0.017). In the control group, 11/35 (31%) developed CN, as demonstrated by a >/=25% fall in GFR, while only one patient in the theophylline group had a fall in GFR (P=0.004). None of the pre-angiographic variables could predict the development of CN. CONCLUSIONS: Following the use of high-osmolar contrast media for routine CAG, CN may develop in 31% of diabetic patients. Patients who received prophylactic oral theophylline had a significantly lower risk of CN than those who did not.     

厄贝沙坦对糖尿病肾病大鼠病理改变及足细胞凋亡的影响

目的 观察厄贝沙坦对糖尿病肾病大鼠病理改变及足细胞凋亡情况的影响,探讨厄贝沙坦对糖尿病肾损伤的保护作用机制.方法 腹腔注射链脲佐菌素建立糖尿病肾病大鼠模型.将36只雄性Wistar清洁级健康大鼠按随机数字表法分为正常对照组(N组)、糖尿病肾病组(DN组)和厄贝沙坦干预组(E组),于用药第12周取肾组织行苏木素-伊红染色及PAS染色,光镜下观察各组肾脏病理改变情况,采用TUNEL法计数凋亡足细胞数目.结果 12周时,DM组、E组大鼠24 h尿蛋白定量与N组比较差异有统计学意义(P＜0.01);E组大鼠24 h尿蛋白定量与DM组比较差异有统计学意义(P＜0.01);光镜下各组肾脏病理改变显示,N组大鼠肾小球形态未见异常变化,采用TUNEL法观察足细胞形态结构正常,未见凋亡足细胞;DN组大鼠肾脏体积较N组增大,系膜区增宽,可见不同程度的系膜细胞增生;采用TUNEL法显示足细胞体积肿胀增大,凋亡足细胞数目明显增多(P＜0.01);E组大鼠肾小球毛细血管基底膜增厚明显改善,凋亡足细胞数目较DM组明显减少(P＜0.01).结论 厄贝沙坦对糖尿病肾病的保护作用机制可能是通过改善肾小球滤过膜结构、抑制足细胞凋亡机制来减少糖尿病肾病大鼠大量蛋白尿,改善糖尿病肾病的预后.

Abstract：

Objective To investigate the influnce of irbesartan on the structure of glomerular filtration memberance and apoptosis of podocytes in diabetic nephropathy (DN) rats.Methods Give intraperitoneal injection of streptozotocin(STZ) to establish models of DN rats. 36 male Wistar clean rats were divided the into 3 groups,Normal Comparison group (N group), diabetic nephropathy group (DN group) and treatment group with Irbesartan (50 mg/kg. d E group) . After 12 weeks we observe 24 h urinary Protein count and the pathological changes of the kidney by extracting renal tissue to do HE staining and PAS staining; to count the apoptosis of podocytes of rats using TUNEL method. Results the level of 24 hour Protein in group E and group DM increased compared with those in the group N.,while the level of 24 hour Protein in group E decreased compared with that in the group DN after 12 weeks (P ＜ 0.01). For N group rats: glomerulus shapes are normal by optical microscopes, the structures of the podocytes are normal, using TUNEL method and there is no apoptotic podocytes. For DM group rates, the volume of kidney is bigger than N group under optical microscope, mesangial region becomes wider and there is different degrees of mesangial hyperplasia. Apoptotic podocytes increased than that of N group( P ＜ 0.01). As for the E group, basement membrane of glomerulus capillary improved significantly, the number of apoptotic podocytes decreased noticeably compared with those of the DM group (P ＜ 0.01). Conclusion The protection mechanism of the irbesartan to the diabetic nephropathy (DN) is probably through the improvement of the structure of glomerular filtration memberance, refraining the mechanism of the apoptosis of podocytes.     

Fas-induced apoptosis is a feature of progressive diabetic nephropathy in transgenic (mRen-2)27 rats: attenuation with renin-angiotensin blockade

BACKGROUND AND AIM: Tubular atrophy is a major feature of most renal diseases and is closely associated with the loss of renal function. The present study sought to investigate whether Fas/FasL-induced tubular epithelial cell apoptosis was a feature of experimental diabetic nephropathy. The effects of renoprotective therapy with blockade of the renin-angiotensin (RAS) system were also examined. METHOD: Six-week-old female Ren-2 rats were injected with streptozotocin and maintained diabetic for 12 weeks. Further groups of diabetic rats were treated with the angiotensin-converting enzyme inhibitor, perindopril, for 12 weeks. RESULTS: Widespread apoptosis, identified by using mediated Terminal dUTP nick-end labelling (TUNEL) staining was noted in the tubules of diabetic Ren-2 rats. These changes were associated with an increase in both Fas mRNA and Fas L (ligand) within the tubules (P < 0.01). Treatment of diabetic Ren-2 rats with perindopril (6 mg/kg per day) reduced the apoptosis to control levels and was associated with a reduction in Fas mRNA and Fas L protein (P < 0.05). CONCLUSION: In conclusion, Fas/Fas L-induced tubular apoptosis is a feature of diabetic Ren-2 rats and is attenuated by the blockade of the RAS.     

表观遗传修饰在糖尿病肾病发病机制中的作用研究进展

"代谢记忆"现象是导致糖尿病并发症发病率持续增高的重要原因,其分子机制的研究主要聚焦在表观遗传修饰。表观遗传修饰在糖尿病肾病的纤维化、炎症、氧化应激、糖代谢及脂代谢紊乱等发病机制中有重要的作用。本文就该机制做一综述,并为进一步的分子研究、诊断及治疗提供新思路。     

Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats

Background. Recent data suggest that aldosterone antagonistshave beneficial effects on diabetic nephropathy. In this study,we investigated the dose-dependent effect of eplerenone anda combined treatment with eplerenone and enalapril comparedwith each drug alone on renal function in type II diabetic rats.To further explore the molecular mechanism of action of combinationtherapy, we also performed in vitro study. Methods. The animals were divided into six groups as follows:normal control Long-Evans Tokushima Otsuka (LETO) rats, OtsukaLong-Evans Tokushima Fatty (OLETF) rats, OLETF rats treatedwith low dose of eplerenone (50 mg/kg/day), OLETF rats treatedwith high dose of eplerenone (200 mg/kg/day), OLETF rats treatedwith enalapril (10 mg/kg/day) and OLETF rats treated with acombination of both drugs (eplerenone 200 mg/kg/day and enalapril10 mg/kg/day) for 6 months. Results. Treatment of OLETF rats had no significant effect onbody weight, kidney weight and blood glucose levels. However,urinary albumin excretion, glomerular filtration rate and glomerulosclerosiswere significantly improved in the enalapril group and improvementwas observed in a dose-dependent manner in the eplerenone groups;the most dramatic decreases were observed in the combinationgroup. In accordance with these findings, renal expressionsof TGF-β1, type IV collagen and PAI-1 were also markedlydecreased in the treatment groups, with the combined treatmentproviding the most significant level of improvement. In culturedmesangial cells, combined treatment resulted in an additivedecrease in TGF-β1, PAI-1 and collagen gene expressionsand protein production induced by high glucose and aldosteronestimulation. Conclusions. Aldosterone receptor antagonism provided additionalbenefits beyond blockade of the renin–angiotensin systemin type II diabetic nephropathy.     

Genetics of diabetic nephropathy in type 2 DM: candidate gene analysis for the pathogenic role of inflammation

SUMMARY:   Hypertension, poor glycemic control and albuminuria are well known risk factors for diabetic nephropathy, but these factors do not explain all of the inter-individual variabilities in the rate of progression to kidney failure. Recent evidence showed that genetic predisposition affected the hyperglycemia-induced nephrotoxicity in patients with type 2 diabetes mellitus (DM). We reviewed the present state of knowledge concerning the relationship between genetics and diabetic nephropathy in type 2 DM. However, the results are inconclusive and the genetic determinants of diabetic nephropathy are not fully understood. In addition, genetic background of nephropathy in type 2 DM was thought to be more complex than in type 1 DM. Recent studies suggested that the inflammation would be an essential component of type 2 DM and its complications. We postulated that increased systemic and/or intrarenal inflammation in high glucose milieu is important in the pathogenesis of nephropathy in patients with type 2 DM. To investigate the impact of inflammation on diabetic nephropathy, we studied several polymorphisms in genes encoding inflammatory cytokine and chemokine in patients with type 2 DM. Among them, −511 C/T in interleukin-1β (IL-1β), tandem repeat in IL-1 receptor antagonist (IL-1Ra), −308 G/A in tumour necrosis factor-α (TNF-α) were significantly associated with an increased risk of kidney failure. In addition, some of them were remarkably different from those previously reported in the NCBI or literature based on the western population.
Our results suggest that inflammation could play a pathogenic role in diabetic nephropathy in type 2 DM. A better understanding of genetic factors predisposing to diabetic nephropathy would not only help to identify diabetic patients at risk, but also be helpful to unveil the pathogenesis of DN.