The “flip-flop” of aldose reductase gene in diabetic retinopathy and nephropathy

Retinopathy and nephropathy - current view

The Kumamoto and UKPDS studies of type-2 diabetes demonstrated that high glucose mean faster worsening for both diabetic retinopathy and nephropathy. However, why so many type-2 diabetics develop nephropathy but no retinopathy? Why so many type-2 diabetics have severe retinopathy and little or no nephropathy? The answer may be genetic susceptibility.

Hypothesis: the “flip-flop” effect of aldose reductase gene

When the CC genotype (high aldose reductase expression) of the (−106) polymorphism of the aldose reductase gene was linked to enhanced retinal susceptibility to hyperglycemia, it was expected that it would also accelerate nephropathy. As the case was the opposite, we now hypothesize that in the kidney, higher aldose reductase activity reduces susceptibility to hyperglycaemia by means of shifting glucose away from the synthesis of Transforming Growth Factor-Beta (TGF-β), a stimulator of mesangial expansion - the landmark of diabetic nephropathy. As the CT & TT genotypes (lower expression of aldose reductase) have effects that are the opposite of those of CC genotype, i.e. retinopathy-protection & nephropathy proneness, we have coined the term “flip-flop”, an acronym taken from electronics, meaning a system that is bi-stable.

If the “flip-flop” was confirmed - what then?

Those diabetics who are retinopathy-protected & nephropathy-prone (CT & TT), should not be given aldose reductase inhibitors (which could worsen nephropathy) but the new breed of TGF-β inhibitors. This might be a first step towards “genetic individualization of diabetes therapy”.     

Lepidium sativum alleviates diabetic nephropathy in a rat model by attenuating glucose levels,oxidative stress,and inflammation with concomitant suppression of TGF-β1

In this research, the treatment of diabetic nephropathy in rats induced by streptozotocin with L. sativium whole-plant aqueous extract was examined, and the mechanism of action was proposed. Adult male rats were grouped into: control, L. sativum, T1DM, and T1DM + L. sativum-treated groups. For 8 weeks, L. sativum S was given to rats at a final dose of 250 mg/kg. Treatment with L. sativum reduced the amount of fasting glucose, increased the amount of fasting insulin, and diminished the increase in hepatic and serum cholesterol, free fatty acid, and triglyceride levels. The level of serum LDL-c was reduced. At the level of the kidney, L. sativum reduced urine volume and albumin excretion and spiked creatinine excretion. It also attenuated the tubular damage in the rats’ kidneys and reduced the amounts of major inflammatory markers, including nuclear factor-kappaα (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Interestingly, L. sativium reduced the amount of mRNA transforming growth factor-β1 (TGF-β1), stimulated mRNA superoxide dismutase (SOD) and catalase (CAT), reduced lipid peroxide levels (MDA), and increased the glutathione (GSH), SOD, and CAT in the rat kidneys of the control and T1DM-treated group. In conclusion, L. sativum is a novel therapy against DN owing to its hypoglycemic effect, insulin-releasing, and antioxidant potential.     

In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker

This study was undertaken to evaluate oxidative stress in the kidney of diabetic mice by electron spin resonance (ESR) imaging technique. Oxidative stress in the kidney was evaluated as organ-specific reducing activity with the signal decay rates of carbamoyl-PROXYL probe using ESR imaging. The signal decay rates were significantly faster in corresponding image pixels of the kidneys of streptozotocin-induced diabetic mice than in those of controls. This technique further demonstrated that administration of angiotensin II type 1 receptor blocker (ARB), olmesartan (5 mg/kg), completely restored the signal decay rates in the diabetic kidneys to control values. In conclusion, this study provided for the first time the in vivo evidence for increased oxidative stress in the kidneys of diabetic mice and its normalization by ARB as evaluated by ESR imaging. This technique would be useful as a means of further elucidating the role of oxidative stress in diabetic nephropathy.     

冠状动脉介入术中对比剂应用对肾功能影响的研究

目的:观察冠状动脉介入术后患者肾功能变化情况、CIN发生率及其相关危险因素。方法:选择从2009年12月至2010年3月在新疆维吾尔自治区人民医院心内科接受冠状动脉介入术的患者131人,测定介入术前5天内任何一天和术后48小时的Scr,分析CIN危险因素。结果:131例患者中有8例发生CIN,发病率为6.1%,Logistic多因素回归分析均显示糖尿病、年龄大于70岁、LVEF小于45%是CIN发生的独立危险因素。结论:糖尿病、LVEF<45%、年龄>70岁是CIN的独立危险因素。     

阿魏酸钠联合缬沙坦对糖尿病肾病患者的疗效及对肾脏纤维化的影响

目的:研究阿魏酸钠联合缬沙坦对糖尿病肾病(diabetic kidney disease,DKD)患者的治疗效果及对肾脏纤维化的影响。方法:选择2017年1月～2018年12月山西医科大学附属晋中医院收治的101例糖尿病肾病患者,随机分为两组。两组均低蛋白饮食,口服他汀类药物调脂,口服降糖药和(或)胰岛素控制血糖。对照组加服缬沙坦8 0 mg/d治疗,观察组服缬沙坦联合静脉滴注0.3 g的阿魏酸钠,每天1次。两组均连续治疗1个月。观察两组肾功能指标、血糖指标以及肾脏纤维化指标的变化。结果:治疗后,观察组的治疗总有效率92.00%(46/50),显著高于对照组[68.63%(35/51)](P0.05)。治疗后,两组患者血清的纤维化相关指标Ⅲ型前胶原(procollagen typeⅢ,PCⅢ)和Ⅳ型胶原(typeⅣCollagen,CⅣ)均明显降低(P0.05),且观察组的明显低于对照组(P0.05);治疗后,两组的空腹血糖(fasting plasma glucose,FPG)、餐后2 h血糖(2 h plasma glucose,2 h PG)、血尿素氮(blood urea nitrogen,BUN)、血肌酐(serum creatinine,SCr)、β2-微球蛋白(β2-Microglobulin,β2-MG)、24 h尿白蛋白排泄率(24 h urine microalbumin excretion,24 h UAER)均明显降低(P0.05),且观察组的指标均显著低于对照组(P0.05),两组肾小球滤过率(GFR)增高(P0.05),且观察组指标明显高于对照组(P0.05)。结论:阿魏酸钠联合缬沙坦对DKD患者有较好的疗效,能明显延缓机体肾脏纤维化的进展速度,进而有效改善肾功能。     

Reduced immunoglobulin A transcytosis associated with immunoglobulin A nephropathy and nasopharyngeal carcinoma

Polymeric IgA (pIgA) is transcytosed by the pIgA receptor (pIgR) across mucosal epithelial cells. After transcytosis to the apical surface, the extracellular, ligand-binding portion of the pIgR is proteolytically cleaved. A missense mutation in human pIgR, A580V, is associated with IgA nephropathy and nasopharyngeal carcinoma. We report that this mutation reduces the rate of transcytosis of pIgR and pIgA, and seemingly the rate of pIgR cleavage. We propose that the defects in pIgR trafficking caused by the A580V mutation may underlie the pathogenesis of both diseases.     

Pioglitazone ameliorates endothelial dysfunction in obese rats with nephropathy

Endothelial dysfunction is a key event in the development of renovascular complications in the metabolic syndrome. The aim of this study was to elucidate the pathogenetic mechanisms involved in renovascular injuries in the Zucker obese rat, a model of the metabolic syndrome, and to examine the therapeutic effects of pioglitazone, a thiazolidinedione. Obese rats fed high-protein diet (OHP) for 12 weeks exhibited nephropathy and endothelial dysfunction, which were improved by pioglitazone. Accumulation of nitrotyrosine, a tracer of nitrative stress, was increased in aorta of the OHP group. The mRNA expressions of NADPH oxidase components and inducible nitric oxide synthase in the aorta were enhanced in the OHP group. Pioglitazone reduced nitrotyrosine in the aorta of the OHP group, inhibiting the augmented expression levels of both. These results suggest that nitrative stress could cause endothelial dysfunction in the rat model of metabolic syndrome with nephropathy, and that pioglitazone ameliorates these injuries, presumably by reducing nitrative stress.     

Hydrogen Sulfide Alleviates Diabetic Nephropathy in a Streptozotocin-induced Diabetic Rat Model

Accumulating evidence has demonstrated that hydrogen sulfide (H₂S) plays critical roles in the pathogenesis of chronic kidney diseases. This study was designed to investigate whether H₂S has protective effects against diabetic nephropathy. Diabetic rats were induced by intraperitoneal injection of streptozotocin and administrated with H₂S donor NaHS for 12 weeks. Rat glomerular mesangial cells were pretreated with NaHS or MAPK inhibitors (U0126, SP600125, and SB203580) prior to high glucose exposure, and cell proliferation was determined. Our findings suggest that H₂S can improve renal function and attenuate glomerular basement membrane thickening, mesangial matrix deposition, and renal interstitial fibrosis in diabetic rats. H₂S was found to reduce high glucose-induced oxidative stress by activating the Nrf2 antioxidant pathway and to exert anti-inflammatory effects by inhibiting NF-κB signaling. In addition, H₂S reduced high glucose-induced mesangial cell proliferation by blockade of MAPK signaling pathways. Moreover, H₂S was also found to inhibit the renin-angiotensin system in diabetic kidney. In conclusion, our study demonstrates that H₂S alleviates the development of diabetic nephropathy by attenuating oxidative stress and inflammation, reducing mesangial cell proliferation, and inhibiting renin-angiotensin system activity.     

不同血液透析方法对终末期肾病患者钙磷代谢的影响

目的：观察不同血液透析方法对终末期肾病患者钙磷代谢的影响。方法：以120例终末期肾病患者为例,比较3种透析方式：血液透析、血液透析滤过、高通量血液透析（各40例）对终末期肾病患者的钙磷代谢及甲状旁腺素的影响。结果：3组透析方法中,HFHD、HDF组治疗前后血钙、磷含量差异有统计学意义,血钙升高,血磷、甲状旁腺素得到较好的清除（P〈0．05）。结论：HFHD、HDF透析使低钙血症改善,血清磷、PTH下降显著。这说明HF,HD、HDF透析对改善钙磷代谢紊乱有积极作用,能有效预防甲旁亢。