NEPHRIN EXPRESSION IN THE POST-NATAL DEVELOPING KIDNEY IN NORMOTENSIVE AND HYPERTENSIVE RATS

Nephrin is a slit diaphragm protein and its expression in the developing kidney is largely unknown. In this study, we explored the expression of nephrin in the developmental kidney in spontaneously hypertensive (SHR) and in Wistar-Kyoto (WKY) rats at different time points, from day 5 after birth to adulthood. Real time RT-PCR, in situ hybridization and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin in the kidney. SHR had hypertension at week 10 and albuminuria at week 20. Nephrin expression in both SHR and WKY increased from day 5 to adulthood. Furthermore, both gene and protein expression of nephrin were significantly lower in SHR after birth when compared to WKY at the same age. These findings suggest that both in normotensive and hypertensive rats, nephrin expression increased from birth to the adult age and that down-regulation of nephrin in SHR evident from the early developmental kidney to adulthood may contribute to the development of albuminuria in adult SHR.     

Nephrin expression in the post-natal developing kidney in normotensive and hypertensive rats

Nephrin is a slit diaphragm protein and its expression in the developing kidney is largely unknown. In this study, we explored the expression of nephrin in the developmental kidney in spontaneously hypertensive (SHR) and in Wistar-Kyoto (WKY) rats at different time points, from day 5 after birth to adulthood. Real time RT-PCR, in situ hybridization and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin in the kidney. SHR had hypertension at week 10 and albuminuria at week 20. Nephrin expression in both SHR and WKY increased from day 5 to adulthood. Furthermore, both gene and protein expression of nephrin were significantly lower in SHR after birth when compared to WKY at the same age. These findings suggest that both in normotensive and hypertensive rats, nephrin expression increased from birth to the adult age and that down-regulation of nephrin in SHR evident from the early developmental kidney to adulthood may contribute to the development of albuminuria in adult SHR.     

Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics

Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.     

自发性高血压大鼠心脏重构与ACE2 mRNA的表达

目的:观察不同月龄的自发性高血压大鼠(SHR)的心脏血管紧张素转换酶2(ACE2)mRNA表达水平,探讨心脏重构与ACE2的内在联系。方法:将12周龄雄性SHR 18只和12周龄WKY Wistar-Kyoto rats大鼠18只随机分为两组,从WKY大鼠组和SHR组中各抽取9只处死,剩余的9只再喂养12周后处死。测量大鼠心脏的质量(HW)与体质量(BW)并计算HW/BW的比值。以实时定量RT-PCR法检测ACE2 mRNA的表达。结果:①与同周龄WKY大鼠组比较,SHR组HW/BW的比值显著增加(P0.01);与12周龄SHR组比较,24周龄SHR组的HW/BW显著增加(P0.05)。②与同周龄的WKY大鼠组比较,SHR组ACE2 mRNA的表达显著降低(P0.01);与12周龄的SHR组比较,24周龄的SHR组ACE2 mRNA的表达显著降低(P0.01)。结论:自发性高血压大鼠心脏重构伴随着心脏中ACE2 mRNA的表达下调。     

Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension

Aims/hypothesis. The location of nephrin has been identified as the slit-diaphragm of the glomerular podocyte. Recent evidence suggests that nephrin could play a key role in the function of the glomerular filtration barrier and the development of proteinuria but its status in long-term diabetes is still not understood. We studied the expression of nephrin in a hypertensive model of diabetic nephropathy and investigated the potential influence of angiotensin II blockade on nephrin gene and protein expression. Methods. Streptozotocin-diabetic spontaneously hypertensive rats were given either no treatment or the angiotensin II antagonist, irbesartan, at a dose of 15 mg/kg per day by gavage for 32 weeks. Non-diabetic spontaneously hypertensive rats were used as a control group. Real time RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin. Results. Diabetic spontaneously hypertensive rats developed albuminuria and had a reduction in both gene and protein expression of nephrin when compared with control rats. Irbesartan treatment prevented the development of albuminuria and completely abrogated the down regulation of nephrin in diabetic rats. Conclusion/interpretation. Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney. These changes in nephrin levels were completely prevented by angiotensin II antagonist treatment, suggesting a potential novel mechanism to explain the antiproteinuric effect of agents which interrupt the renin-angiotensin system. [Diabetologia (2001) 44: 874–877] Received: 19 January 2001 and in revised form: 16 March 2001     

Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY

The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG.     

Protein phosphatase 2A B56alpha during development in the spontaneously hypertensive rat

Mistargeting of the regulatory subunit of protein phosphatase 2A (PP2A), B56alpha is involved in the hyperphosphorylation and desensitization of the D1 dopamine receptor in renal proximal tubules of spontaneously hypertensive rats (SHRs). However, the renal expression of B56alpha before hypertension develops is not known. Therefore, we studied the expression of B56alpha and PP2A activity in the kidney during development in the SHR and its normotensive control, the Wistar-Kyoto (WKY) rat. PP2A B56alpha was expressed in proximal and distal tubules with no differences in the pattern of expression in WKY and SHRs at any age. In brush border membranes of renal proximal tubules, PP2A B56alpha protein was greatest in the immature rats and decreased with development. However, PP2A activity did not change with age. PP2A B56alpha protein and PP2A activity were similar in WKY and SHRs except at 2 weeks when both PP2A B56alpha protein and PP2A activity were higher in SHRs than in WKY rats. The PP2A catalytic subunit co-immunoprecipitated with the D1 receptor in renal proximal tubule cells. It is possible that the increased expression of PP2A B56alpha and increased basal PP2A activity in the young, especially in the SHRs, may serve as a compensatory mechanism in the increased phosphorylation and decreased renal D1 receptor function, including D1-receptor mediated stimulation in renal proximal tubules of SHRs.     

Isolation of preferentially expressed genes in the kidneys of hypertensive rats

By differential hybridization, three complementary DNAs designated as S3, S2, and SA were isolated, and the corresponding messenger RNAs (mRNAs) were differentially expressed between the kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. S3 is identical to cytochrome P450 IV A2. SA encoded a protein of 546 amino acid residues, and its carboxyl terminal region had a slight homology to luciferase. No homologous sequence has been reported in S2 sequences. S3 mRNA was about four times more abundantly expressed in the kidneys of 28-day-old SHR than in those of age-matched WKY rats, but there was no difference at age 16 weeks. A low NaCl diet positively modulated the expression of the S3 gene. S2 mRNA was almost undetectable in the kidneys of 28-day-old WKY rats but was clearly detected in those of age-matched SHR. The expression level of S2 mRNA in the livers of 16-week-old SHR was about five times higher than that of age-matched WKY rats. The expression of S2 mRNA in the livers was modulated by dietary NaCl and captopril. SA mRNA was more than 10 times more abundantly expressed in the kidneys of SHR than in those of WKY rats from age 4 weeks. With the administration of captopril, the expressions of SA mRNA in the livers of SHR were positively modulated. Because these three genes are not only differentially expressed between SHR and WKY rats but also related to sodium metabolism or blood pressure control, the identification of these genes may provide important probes to examine the mechanisms of hypertension.     

Improvement of Vascular Remodeling in Spontaneous Hypertensive Rats with Traditional Chinese Medicine

Qin-Dan-Jiang-Ya-Tang (QDJYT) is a traditional Chinese herbal medicine for the treatment of hypertension. The effect of QDJYT on blood pressure (BP) and vascular remodeling in hypertension was investigated in the model of spontaneous hypertensive rats (SHR). Sixteen SHRs were divided into two groups: the SHR group and the SHR+ QDJYT group. Eight Wistar-Kyoto (WKY) rats were in the normal control group. QDJYT (750mg/kg) was orally administered daily for 12 weeks to the SHR+QDJYT group. After 12 weeks, thoracic aortas were segregated. The media thickness (MT) and the lumen diameter (LD) of the aortic wall, the ratios of MT to LD, the expression of basic fibroblast growth factor (bFGF) mRNA, and the level of its proteinic production were examined by histology, real-time PCR, and Western blot analysis, respectively. It was observed in our study that MT, MT/LD, the expression of bFGF mRNA, and the level of its proteinic production in aortic walls were higher in SHRs than in WKY rats. However, in the SHRs treated with QDJYT, we found MT, MT/LD, the expression of bFGF mRNA and the level of its proteinic production were lower than SHRs. These results suggest that QDJYT can improve the vascular remodeling in SHRs, and the mechanisms may be related to the suppressive effect of QDJYT on bFGF mRNA and its proteic productions in the aortic walls of SHRs.     

Cerebrovascular and brain microanatomy in spontaneously hypertensive rats with streptozotocin-induced diabetes

The influence of hypertension associated with diabetes on cerebrovascular and frontal cortex or hippocampus microanatomy was investigated in 20-week-old spontaneously hypertensive rats (SHR) in which diabetes was induced by treatment with streptozotocin (STZ) and in control or STZ-diabetic age-matched normotensive Wistar Kyoto (WKY) rats. At the beginning of experiment, systolic pressure values were similar in WKY rats either control, or exposed to STZ and remarkably higher in control or STZ-treated SHR. Systolic pressure values increased in the different animal groups examined along the course of experiment. Blood glucose levels were increased in either STZ-WKY rats or -SHR compared to WKY rats and SHR respectively. The main changes occurring in pial and intracerebral arteries of SHR and STZ-SHR were thickening of the arterial wall accompanied by luminal narrowing. In medium sized pial arteries of STZ-WKY rats luminal narrowing and a decreased thickness of arterial wall were noticeable. Intracerebral arteries of STZ-WKY diabetic rats showed a not homogeneous sensitivity of different sized branches. The volume of zones III and IV of frontal cortex was decreased in SHR and STZ-SHR compared to control WKY rats. The number of nerve cells in these cerebrocortical layers was decreased to a similar extent in SHR. STZ-WKY rats or STZ-SHR compared to control WKY rats. In dentate gyrus, followed by the CA1 subfield of hippocampus, decreased volume and number of neurons were found in SHR and STZ-SHR compared to control WKY rats. The occurrence of astrogliosis was observed in hypertensive, diabetic or hypertensive plus diabetic rats. The above findings indicate the occurrence of cerebrovascular and brain microanatomical changes in SHR and to a lesser extent in STZ-diabetic rats compared to control normotensive and normoglicemic WKY rats. Association of hypertension and diabetes caused more pronounced changes than in the single disease models. These results support the view that hypertension and diabetes affect the structure of cerebrovascular tree and of brain and that association of the two diseases results in an increased risk of target-organ damage, involving brain.     

The presence of genetic hypertension stimulates early renal accumulation of fibronectin in experimental diabetes mellitus

Aims/hypothesis: To investigate the interaction between hypertension and diabetic nephropathy, we studied the renal accumulation of fibronectin in a genetic model of hypertension with streptozotocin-induced diabetes mellitus. Methods: Spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar Kyoto rats (WKY) were studied at 4 weeks of age. The rats were killed 20 days after the induction of diabetes mellitus. The renal accumulation of fibronectin was estimated using Western blot analysis as well as immunofluorescence technique and confocal microscopy. Results: Blood glucose concentrations were similar in diabetic SHR rats (27 ± 3.3 mmol/l) and WKY rats (25.5 ± 2.7 mmol/l). The systolic blood pressure was higher in both groups of SHR rats than in the control rats. The abundance of renal fibronectin as detected by Western blot analysis was (p < 0.05) higher in the diabetic SHR rats (41.4 ± 15.0 densitometric U, n = 8) than in the control rats, and no difference was observed between diabetic and control WKY rats (20.8 ± 6.2, n = 8) and (27.8 ± 17.2, n = 8). The mean peak intensity of fibronectin signal within the glomerulus as estimated by confocal microscopy was higher (p < 0.05) in the diabetic SHR rats (32.9 ± 3.5) than in control SHR rats (11.9 ± 5.7) or diabetic (7.4 ± 2.2) and control (15.2 ± 7.9) WKY rats. Conclusion/interpretation: In experimental diabetes the presence of genetic hypertension promotes earlier accumulation of renal fibronectin, a matrix protein implicated in renal glomerulosclerosis. [Diabetologia (2001) 44: 2088–2091] Received: 11 January 2001 and in revised form: 30 May 2001     

Improvement of vascular remodeling in spontaneous hypertensive rats with traditional Chinese medicine

Qin-Dan-Jiang-Ya-Tang (QDJYT) is a traditional Chinese herbal medicine for the treatment of hypertension. The effect of QDJYT on blood pressure (BP) and vascular remodeling in hypertension was investigated in the model of spontaneous hypertensive rats (SHR). Sixteen SHRs were divided into two groups: the SHR group and the SHR+ QDJYT group. Eight Wistar-Kyoto (WKY) rats were in the normal control group. QDJYT (750 mg/kg) was orally administered daily for 12 weeks to the SHR+QDJYT group. After 12 weeks, thoracic aortas were segregated. The media thickness (MT) and the lumen diameter (LD) of the aortic wall, the ratios of MT to LD, the expression of basic fibroblast growth factor (bFGF) mRNA, and the level of its proteinic production were examined by histology, real-time PCR, and Western blot analysis, respectively. It was observed in our study that MT, MT/LD, the expression of bFGF mRNA, and the level of its proteinic production in aortic walls were higher in SHRs than in WKY rats. However, in the SHRs treated with QDJYT, we found MT, MT/LD, the expression of bFGF mRNA and the level of its proteinic production were lower than SHRs. These results suggest that QDJYT can improve the vascular remodeling in SHRs, and the mechanisms may be related to the suppressive effect of QDJYT on bFGF mRNA and its proteic productions in the aortic walls of SHRs.     

硫化氢对自发性高血压大鼠血管炎症反应的调节作用

目的 探讨新型气体信号分子硫化氢(H2S)对自发性高血压大鼠(SHR)血管炎症反应的调节作用.方法 4周龄Wistar-Kyoto(WKY)雄性大鼠和SHR雄性大鼠分为4组:WKY大鼠对照组、SHR对照组、SHR+硫氢化钠(NaHS,H2S供体)组及SHR+炔丙基甘氨酸(PPG,H2S生成关键酶抑制剂)组,饲养至9周.尾容积法测清醒时大鼠血压,免疫组织化学方法检测主动脉内皮细胞膜细胞间黏附分子-1(ICAM-1)、核转录因子-κB p65(NF-κB p65)和核转录因子抑制因子-α(IκB-α)的蛋白表达,原位杂交分析检测主动脉内皮细胞ICAM-1 mRNA的表达.结果 SHR对照组血压显著高于WKY对照组(P<0.05),主动脉内皮细胞ICAM-1、ICAM-1 mRNA、胞核NF-κB p65明显高(P均<0.01),胞浆IκB-α蛋白表达明显低(P<0.01).SHR+NaHS组血压显著低于SHR对照组,主动脉内皮细胞ICAM-1、ICAM-1 mRNA、胞核NF-κB p65蛋白表达明显低(P<0.05),胞浆IκB-α蛋白表达明显增高(P<0.05),SHR+PPG组主动脉内皮细胞ICAM-1、ICAM-1mRNA、胞核NF-κB p65蛋白表达更高(P<0.05),胞浆IκB-α蛋白表达显著低(P<0.05).结论 H2S可通过抑制SHR血管炎症发挥抗高血压效应.H2S的抗血管炎症效应可能通过上调IκB-α的表达,降低NF-κB p65的表达,抑制ICAM-1 mRNA的转录和蛋白表达实现.     

Diabetes-induced alterations in atrial natriuretic peptide gene expression in Wistar-Kyoto and spontaneously hypertensive rats

We investigated the effects of streptozotocin-induced diabetes on atrial natriuretic peptide (ANP) synthesis, hemodynamic parameters, blood volume, and histopathology, as well as the reversibility of such effects with insulin therapy in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The biatrial ANP messenger RNA (mRNA) levels in the diabetic WKY rats increased by 16-17% compared with those in the age-matched WKY rats at 12 weeks after the onset of diabetes, whereas their ventricular ANP mRNA levels showed increases of 190% in left ventricles and 160% in right ventricles at 8 weeks. In the diabetic SHRs, the left atrial ANP mRNA levels increased by 36% compared with those in the age-matched SHRs, as early as 4 weeks after diabetes onset. Their ventricular ANP mRNA levels also showed 80-82% increases in left and right ventricles at 4 weeks. In proportion to changes in cardiac ANP synthesis, the biventricular end-diastolic pressures were significantly elevated at 8 weeks in the diabetic WKY rats and at 4 weeks in the diabetic SHRs. The blood volume significantly increased at 8 weeks in the diabetic WKY rats and remained higher thereafter, whereas it did not change in the diabetic SHRs throughout the experimental period. The left ventricular peak dP/dt was depressed in the 8-week diabetic SHRs, whereas in the diabetic WKY rats, its depression was observed at 12 weeks after diabetes onset. Histopathological studies showed that diabetic changes in ANP synthesis and hemodynamic parameters described above occurred before the cardiomyopathic histological changes. Cardiac ANP synthesis in the diabetic rats completely reverted to control levels after insulin therapy, accompanied by normalization of hemodynamic parameters. The present study indicates that 1) ANP synthesis is significantly augmented in the streptozotocin-induced diabetic rat compared with that in the normal rat, and the combination of diabetes and hypertension produces an earlier and greater effect in stimulating cardiac ANP synthesis than does either disease alone; 2) an elevation in the intraventricular filling pressure that occurs before observable cardiomyopathic histopathological alterations might be involved partially in the augmented ANP synthesis; and 3) the reversibility with insulin therapy suggests that the streptozotocin-induced alterations observed in cardiac ANP synthesis and hemodynamics result from insulin-deficient diabetes mellitus, not from cardiac toxicity of streptozotocin.     

Genetic hypertension accelerates nephropathy in the streptozotocin diabetic rat

To evaluate whether hypertension is a cause or just an association with diabetic renal disease, diabetes was induced in both normotensive Wistar-Kyoto and spontaneously hypertensive rats (WKY and SHR). Animals were assessed monthly for 8 months before sacrifice. When compared to normotensive diabetic rats (WKY-STZ), hypertensive diabetic rats (SHR-STZ) had an earlier and more rapid rise in urinary albumin excretion. In addition, SHR-STZ had increased glomerular basement membrane thickness when compared to WKY-STZ or SHR. In a separate experiment, Enalapril therapy (35 mg/L) was administered in drinking water to WKY-STZ and SHR-STZ. Enalapril significantly reduced blood pressure in both animal groups, and this was associated with a decrease in urinary albumin excretion. The SHR-STZ model has accelerated nephropathy as determined by both functional and structural parameters. Angiotensin-converting enzyme inhibition is associated with a reduction in albuminuria in both hypertensive and normotensive models of diabetic nephropathy.     

Protein Phosphatase 2A B56α During Development in the Spontaneously Hypertensive Rat

Mistargeting of the regulatory subunit of protein phosphatase 2A (PP2A), B56α is involved in the hyperphosphorylation and desensitization of the D₁ dopamine receptor in renal proximal tubules of spontaneously hypertensive rats (SHRs). However, the renal expression of B56α before hypertension develops is not known. Therefore, we studied the expression of B56α and PP2A activity in the kidney during development in the SHR and its normotensive control, the Wistar‐Kyoto (WKY) rat. PP2A B56α was expressed in proximal and distal tubules with no differences in the pattern of expression in WKY and SHRs at any age. In brush border membranes of renal proximal tubules, PP2A B56α protein was greatest in the immature rats and decreased with development. However, PP2A activity did not change with age. PP2A B56α protein and PP2A activity were similar in WKY and SHRs except at 2 weeks when both PP2A B56α protein and PP2A activity were higher in SHRs than in WKY rats. The PP2A catalytic subunit co‐immunoprecipitated with the D₁ receptor in renal proximal tubule cells. It is possible that the increased expression of PP2A B56α and increased basal PP2A activity in the young, especially in the SHRs, may serve as a compensatory mechanism in the increased phosphorylation and decreased renal D₁ receptor function, including D₁‐receptor mediated stimulation in renal proximal tubules of SHRs.     

亚硒酸钠对糖尿病肾病大鼠肾脏脂联素和nephrin表达的影响

目的 探讨亚硒酸钠对糖尿病肾病大鼠肾脏脂联素和nephrin表达的影响及其相互间的关系,从而研究亚硒酸钠与脂联素、nephrin在糖尿病肾病中的作用机制.方法 通过链脲佐菌素法加高脂饮食诱导模拟大鼠糖尿病肾病模型,实验设完全空白对照组、糖尿病组、糖尿病药物干预组,药物干预组每日给予亚硒酸钠溶液灌胃,其它组给予等量盐水溶液灌胃.10周后处死大鼠,取血、尿标本测相关生化指标,取肾脏组织分别提取DNA和蛋白质标本,石蜡切片光镜观察病理改变及免疫组化分析蛋白表达定位,实时定量PCR法检测脂联素mRNA表达、RT-PCR法检测nephrin mRNA表达,Western印迹法检测脂联素和nephrin蛋白表达.结果 亚硒酸钠干预组大鼠生化指标较糖尿病组明显改善,光镜下观察亚硒酸钠干预组病理改变较糖尿病组明显减轻.免疫组化分析,亚硒酸钠干预组脂联素蛋白着色较糖尿病组明显增强,且肾小管、肾小球内均有着色;糖尿病组nephrin蛋白表达着色较空白对照组减少,亚硒酸钠干预组较糖尿病组着色明显增多.亚硒酸钠干预组脂联素mRNA和蛋白表达明显高于糖尿病组和正常对照组,差异有统计学意义(均P＜0.05).亚硒酸钠干预组nephrin mRNA和蛋白表达均较糖尿病组明显增加,但仍较空白对照组降低,差异均有统计学意义(P＜0.05).结论 亚硒酸钠能促进大鼠肾脏脂联素和nephrin表达,表明亚硒酸钠、脂联素和nephrin在延缓和防治糖尿病肾病的发生发展中可能起重要作用.     

Early short-term treatment with exogenous hydrogen sulfide postpones the transition from prehypertension to hypertension in spontaneously hypertensive rat

Hydrogen sulfide (H₂S), nitric oxide (NO), and renin–angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H₂S donor, can regulate H₂S-generating pathway, NO pathway, and the RAS, to prevent the transition from prehypertension to hypertension in spontaneously hypertensive rats (SHRs). Four-week-old SHRs and control normotensive Wistar–Kyoto (WKY) rats were assigned into three groups: WKY, SHRs, and SHR + NaHS; SHRs were injected intraperitoneally with sodium hydrosulfide (14 μmol/kg/day) for 4 weeks. SHRs exhibited hypertension at 12 weeks of age, which was blocked by early sodium hydrosulfide administration. Concentrations of H₂S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H₂S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma N^G monomethyl-l-arginine (l-NMMA, an inhibitor of NO synthase) level and increases plasma NO level in SHRs. Next, sodium hydrosulfide administration reduces renal mRNA expression of Ren, Atp6ap2, Agt, Ace, and Agtr1a in SHRs. We conclude that early short-term sodium hydrosulfide treatment increases renal H₂S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.