The presence of a juxtaglomerular apparatus in elasmobranch fish

Summary Previous studies have concluded that a juxtaglomerular apparatus evolved in phylogenetic groups higher than elasmobranch fishes. The present study shows for the first time a distinct juxtaglomerular apparatus in four marine elasmobranchs, the spiny dogfish (Squalus acanthias), the smooth dogfish (Mustelus canis), the little skate (Raja erinacea), and the cownose ray (Rhinoptera bonasus). Serial semithin sections of these fishes' kidneys reveal the four morphological components of a juxtaglomerular apparatus at the vascular pole of the renal corpuscle: (1) an afferent arteriole surrounded by smooth muscle cells which have granules containing a material exhibiting a periodic substructure comparable to that of renin granules in higher vertebrates; (2) an efferent arteriole usually devoid of smooth muscle cells but having pericyte-like cells; (3) a macula densa portion of the distal tubule juxtaposed between the afferent and efferent arterioles; and (4) elongated, fusiform cells (Goormaghtigh cells), which are in continuity with similar cells of the abundant intra-glomerular mesangium, and fill the space bordered by the distal tubule and by the afferent and efferent vessels. The distal tubule, from the site where it lies close to the afferent arteriole, moves directly toward the urinary pole, frequently indenting the renal corpuscle. Within this indentation, the tubule may be flanked by the efferent vessel, by the extraglomerular mesangium, or by Bowman's capsule only. Facing these structures the tubular epithelial cells possess basally dilated intercellular spaces. Endothelial cells of the efferent vessel(s) are fenestrated, possessing pores which are closed by a diaphragm. Conclusion: marine elasmobranch fish possess the morphological components of a juxtaglomerular apparatus which suggests that these fishes, like most other vertebrates, possess a renin-angiotensin system and a glomerulartubular feedback mechanism.Fellow of the Alexander von Humboldt Foundation     

The structure of the juxtaglomerular apparatus in Addison's disease,Bartter's syndrome,and in Conn's syndrome

Summary Continuing and supplementing previous morphometric studies on the Juxtaglomerular apparatus (JGA) of normal kidneys we have now investigated semi-thin serial sections of each 10 hyperplastic and hypertrophied JGAs in Addison's disease and in Bartter's syndrome, as well as 8 atrophic JGAs in Conn's syndrome. With the exception of Bartter's syndrome, where in only two out of ten JGAs the efferent arteriole, and in none of them the afferent arteriole touches immediately the macula densa, there is an almost regular direct contact between the hilar arterioles and the macula densa like in normal kidneys. The Goormaghtigh cell field invariably touches the macula densa. In Bartter's syndrome, but not in Addison's disease, a considerable enlargement of the macula densa was measured, associated with an exceptional enlargement of the Goormaghtigh cell field. In all cases examined here about 40–60% of the basal area of the macula densa do not have any direct contact with other structures forming the JGA.Supported by the Deutsche Forschungsgemeinschaft.We thank the colleagues of the Institute of Medical Biometry, University of Tübingen, (head: Prof. Dr. M.-P. Geppert) for making all statistical analyses.     

The juxtaglomerular apparatus in IgA nephropathy: An analysis of the transport and fate of IgA deposits at the glomerular hilus

Summary This study on 27 cases of IgA nephropathy has shown that IgA deposits are rare in the juxtaglomerular apparatus (JGA) despite large amounts of IgA deposits in the mesangium. Phagocytes are absent in JGA. A small number of ill-defined, IgA-positive substances are seen in the matrix of lacis cells, and their electron-density is decreased. These findings indicate dissolution of IgA deposits in the intercellular matrix. In addition, it is suggested that the transport of IgA deposits through the glomerular stalk toward JGA is prevented at the border area between the mesangium of glomerular hilus and the lacis cell region. The block is not complete, because small, IgA-positive substances are seen sparsely in the matrix of lacis cells. The structure of the lacis cell region is thought to restrict the passage of macromolecules such as IgA deposits. Frequently positive staining for C3 in the mesangium and lacis cell region and within the wall of afferent and efferent arterioles indicates that C3 is easily accessible to the arteriolar wall adjacent to JGA, by the route through the glomerular stalk and JGA. This may be concerned in the pathogenesis of arteriolar hyalinosis at the glomerular hilus.     

Lipofuscin-like granules of the juxtaglomerular apparatus of the kidney. The diagnostic significance of a quasi-normal subcellular structure incidentally encountered in the course of routine ultrastructural evaluation of renal biopsies

Lipofuscin-like granules, first described by Biava and West in 1965, are a subcellular, quasi-physiologic finding mainly seen in the smooth muscle cells of renal arterioles, but also in juxtaglomerular cells and the lacis cells of human kidneys. They increase in number in subjects affected by arterial hypertension and diabetes. They do not correlate with a specific primary renal disease. Lipofuscin-like granules are not related to renin granules. The world literature on this subject is almost non-existent, and the awareness of this finding or its clinical significance among either pathologists or nephrologists is very poor. We incidentally observed these lipofuscin-like granules in 8 cases during the routine electron microscope examination of 440 renal biopsies, and report herein on their ultrastructural features. Six of these 8 patients were affected by arterial hypertension, one of whom was also concomitantly affected by diabetes mellitus. These lipofuscin-like granules appear as dense bodies with a lipid component, a coarsely granular matrix, and a crystalloid component which may appear in a band or dot pattern, according to the plane of sectioning. The pathologist has to be aware of these lipofuscin-like granules in order not to confuse them with the semicircularly organized (fingerprint) linear immune deposits associated with some specific glomerulopathies.     

The Tsukuba hypertensive mouse (transgenic mouse carrying human genes for both renin and angiotensinogen) as a model of human malignant hypertension: development of lesions and morphometric analysis

 The renin-angiotensin system has a pivotal role in hypertension. The Tsukuba hypertensive mouse (THM; a transgenic mouse carrying human genes for both renin and angiotensinogen) was generated to allow further examination of the renin-angiotensin system in a variety of pathologic conditions. We evaluated the development of renal lesions in these mice and in controls by morphometric, immunohistochemical and ultrastructural methods. Blood pressure was significantly higher in THM than in control mice; 1 year after birth, it was approximately 40 mmHg higher. The kidney-to-body weight ratio was also higher in THM than in control. Morphometrical analysis revealed that the glomerular sclerosis index was significantly elevated in THM with 10% of the glomeruli sclerotic at 18 months. The grade of vascular lesion and the frequency of fibronoid arteritis of the kidney exhibited the same tendency as the glomerular sclerosis index. Murine renin was located exclusively in the juxtaglomerular apparatus, whereas human renin was expressed not only in the juxtaglomerular apparatus, but also in periarteriolar smooth muscle cells and in mesangial and epithelial cells of the glomeruli. Light and electron microscopy revealed significant fibrinoid arteritis of the kidney in THM and also ”onion skinning”, both pathognomonic for malignant nephrosclerosis. THM may be an excellent model of human malignant hypertension. Received: 22 May 1997 / Accepted: 18 August 1997     

Sex differences in the developmental programming of hypertension

Experimental models of developmental programming provide proof of concept and support Barker's original findings that link birthweight and blood pressure. Many experimental models of developmental insult demonstrate a sex difference with male offspring exhibiting a higher blood pressure in young adulthood relative to their age‐matched female counterparts. It is well recognized that men exhibit a higher blood pressure relative to age‐matched women prior to menopause. Yet, whether this sex difference is noted in individuals born with low birthweight is not clear. Sex differences in the developmental programming of blood pressure may originate from innate sex‐specific differences in expression of the renin angiotensin system that occur in response to adverse influences during early life. Sex differences in the developmental programming of blood pressure may also involve the influence of the hormonal milieu on regulatory systems key to the long‐term control of blood pressure such as the renin angiotensin system in adulthood. In addition, the sex difference in blood pressure in offspring exposed to a developmental insult may involve innate sex differences in oxidative status or the endothelin system or may be influenced by age‐dependent changes in the developmental programming of cardiovascular risk factors such as adiposity. Therefore, this review will highlight findings from different experimental models to provide the current state of knowledge related to the mechanisms that contribute to the aetiology of sex differences in the developmental programming of blood pressure and hypertension.     

The reflex effect of changes in renal perfusion on hindlimb vascular resistance in anaesthetized rabbits

This study was designed to characterise the response of the hindlimb vasculature to reduced renal perfusion in the anaesthetized rabbit and to elucidate whether the stimulus was dependent upon reduced renal perfusion pressure (RPP) or blood flow (RBF). Acute decreases in renal perfusion resulted in rapid and reversible increases in femoral perfusion (FPP). This vascular response was completely abolished following renal denervation indicating that the afferent component of the reflex is neurally mediated. Acute hindlimb responses to changes in renal perfusion pressure were present whether the limb was perfused with homologous blood or cross-perfused with blood from a donor rabbit, demonstrating that the efferent component of the response is also neurally mediated. There was a 28-s latency for initiation of the hindlimb vasoconstriction, which is consistent with recent evidence for renal autocoid stimulation of the afferent renal nerve receptors. Decreasing RPP indirectly, by altering flow, resulted in a hindlimb vasoconstriction below approximately 55 mm Hg (7.3 kPa) RPP or 15 ml/ min RBF. However, decreasing RPP by directly reducing pressure in graded steps resulted in increases in FPP, which reflected the changes in renal flow; thus during the autoregulatory phase, where flow did not change as pressure fell, FPP also remained stable. The results of these protocols suggest that a neurally mediated hindlimb vascular reflex is stimulated by decreased renal flow rather than pressure.     

The effect of renal sympathectomy on blood pressure and plasma renin activity in spontaneously hypertensive and normotensive rats

Renal denervation delays the development of hypertension in spontaneously hypertensive (SH) rats. The influence of bilateral surgical renal sympathectomy, verified by fluorescence microscopy, on blood pressure and plasma renin activity in SH and normotensive rats (170–180 g before the sympathectomy) was studied. Neither in SH nor in normotensive rats, did the preoperative systolic blood pressure in the renal-sympathectomized group differ from that in the sham-operated controls. After the sympathectomy, blood pressure in the SH rats increased in 4 weeks only insignificantly, from 160±3 to 172±6 mmHg, while that in the sham-operated SH rats rose from 163±5 to 191±5 mmHg. In normotensive rats, blood pressures in both the renal-sympathectomized and sham-operated groups remained at the pre-operative levels. Thirty days after the operations, plasma renin activity or plasma kininogen in the renal-sympathectomized group did not differ from that in the sham-operated one either in SH or in normotensive rats. The results suggest that the delay in hypertension development produced by renal sympathectomy in SH rats is not mediated by a reduction in renin secretion.     

老年收缩期高血压的血压昼夜节律和血压负荷值与靶器官损害的关系

目的评价老年收缩期高血压(ISH)的动态血压(ABP)节律及负荷值对靶器官的影响.方法106例60岁以上收缩压≥21.28kPa和舒张压(DBP)≤12.64kPa的患者分为两组Ⅰ组(无靶器官损害者39例)和Ⅱ组(合并心、脑、肾损害,但处于功能代偿期67例).分别选30例正常血压的老年人和中青年(≤55岁)为对照组(EC和MC).所有病例均作ABP监护.结果EC、MC、Ⅰ组和Ⅱ组相比,ABP节律异常者逐渐增加,昼夜血压差值逐渐缩小.与Ⅰ组比,Ⅱ组白昼与夜间(尤其是夜间)SBP平均值和负荷值显著增高.各组DBP平均值及负荷值差异不显著.结论老年ABP减弱甚至消失,合并ISH时这种变化更明显,老年ISH的异常血压节律和持续(尤其是夜间)SBP升高及超负荷与靶器官损害有关.     

The influence of high salt intake and/or chronic blood volume expansion on renin-angiotensin system in Brattleboro rats

The influence of chronic saline drinking and/or DOCA-salt treatment on plasma renin activity and renal renin concentration was studied in vasopressin-deficient homozygous (DI) Brattleboro rats and their vasopressin-secreting heterozygous (non-DI) littermates. The activity of renin-angiotensin system (RAS) can be suppressed even in the absence of vasopressin under the conditions of a sufficiently high salt intake that is achieved in DI rats by consumption of 0.6% saline instead of water. An almost complete RAS suppression in both plasma and kidney was observed in young animals in which high salt intake induced not only blood volume expansion but also blood pressure elevation, i.e. in mildly hypertensive unilaterally nephrectomized saline drinking DI rats as well as in moderately hypertensive DOCA-salt treated DI rats and in non-DI rats with a severe DOCA-salt hypertension. Our results indicate that intravascular expansion and blood pressure changes are important factors for the modulation of plasma and renal renin activity even in the absence of vasopressin.     

Gender-specific combined effects of smoking and hypertension on cardiovascular disease mortality in elderly Koreans: The Kangwha Cohort Study

Objective

We examined gender-specific combined effects of smoking and hypertension on risk of mortality from cardiovascular disease in elderly Korean men and women.

Study design

This study followed a cohort of 6097 residents (2593 men, 3504 women) in the general population of Kangwha County, aged ≥55 years in March 1985 and examined their cause-specific mortality for 20.8 years, up to December 31, 2005. All participants were followed up more than once after the 1985 survey.

Main outcome measures

We calculated hazard ratios for mortality for the combined sets of smoking habits and blood pressure levels using the Cox proportional-hazard model. The set of non-smokers with normal blood pressure served as a reference group.

Results

During the 20.8 years of follow-up, 759 people died from cardiovascular disease. The risk of mortality from cardiovascular disease and stroke according to smoking or hypertension was not different between men and women. However, the risk among smokers combined with hypertension was higher in men than in women; the multivariable-adjusted hazard ratios (95% CI) for mortality from cardiovascular disease and stroke were 4.52 (1.67–12.21) and 6.37 (1.57–25.85) in men and 2.11 (1.37–3.24) and 2.41 (1.44–4.01) in women, respectively.

Conclusions

The magnitude of the joint effects of smoking and hypertension on cardiovascular disease and stroke mortality was different between men and women. This study suggests that combining quitting smoking with lowering blood pressure could contribute to preventing cardiovascular disease and stroke, especially in men.     

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.     

Metabolic syndrome component combinations and chronic kidney disease: The severance cohort study

Objectives

The effects of ethnicity and gender can produce varying results when evaluating risk of chronic kidney disease (CKD) development and metabolic syndrome (MetS) components. The risks of specific MetS component combinations and incident CKD are unclear. The aim of this study was to investigate the relationship between the combination of MetS components and CKD.

Methods

This prospective cohort study included 15,401 participants. Koreans 20–84 years of age were followed for 5.2 years. The NCEP-ATP III definition of MetS was used. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m² by the simplified Modification of Diet in Renal Disease equation.

Results

The incidence rate per 1000 person-years of CKD was determined in men (13.8) and women (14.1) with MetS. In a multivariate Cox proportional hazard model controlling for age and lifestyle variables, increased CKD risk in men (hazard ratio 1.45, 95% confidence interval 1.20–1.76) and women (1.52, 1.19–1.93) with Mets was found compared to those without MetS. Incidence and HRs for CKD elevated with increasing numbers of MetS components in men and women (P for trend <0.0001). The risks associated with MetS varied by combination of causative factors. High blood pressure (BP) and low high-density lipoprotein (HDL) were more likely to be associated with risk of CKD development.

Conclusions

BP and HDL were the leading risk factors for CKD development in healthy Koreans. The association between MetS and kidney dysfunction were significantly independent of traditional cardiovascular risk factors.     

Effect of alteration of peripheral blood flow on the central circulation in man during supine cycling in different ambient temperatures

Summary Whether the alteration of peripheral circulation caused by changing ambient temperature (T_a) affects central circulatory changes in man during supine cycling was investigated in four well-trained men, who exercised at two levels (117.7 or 176.6 W). Exercise metabolic rate (VO₂) in cold (0 C or 10 C) was the same as it was at 20 C, whereas the cardiac output (CO; CO₂ rebreathing technique) and heart rate were significantly lower (e.g., 176.6 W at 0 C, both p<0.01). In heat (30 C or 40 C), the VO₂ reduced with falling CO and mean arterial blood pressure from those at 20 C (e.g., 176.6 W at 40 C, all cases p<0.01), whereas the peak post-exercise calf blood flow (CBF_p) increased (p<0.01). The VO₂ and stroke volume (SV) were inversely proportional to the ratio of CBF_p to CO/kg body weight (CBF_p/CO) (r>–0.78, p<0.001). Total peripheral resistance (TPR) was related to arteriovenous oxygen difference (A-VO₂ difference) (r>0.78, p<0.001). The TPR and A-VO₂ difference decreased as T_a rose, while CBF_p/CO was almost the same. As CBF_p/CO had exceeded 50 and further progressed, however, the two parameters elevated until the same level as that at 0 C. The present results suggest that during moderately prolonged (16–60 min) supine cycling in different T_a's the central circulatory changes are mainly affected by the altered peripheral blood flow in competing between skin and muscle for blood flow.     

Phenotypes,accumulation, and functions of myeloid-derived suppressor cells and associated treatment strategies in cancer patients

Myeloid-derived suppressor cells (MDSCs) comprise a group of heterogeneous and immature myeloid-derived cells. MDSCs accumulate in the blood, lymphoid organs, spleens and tumor tissues under different pathogenic conditions such as infection, trauma, hematosepsis, and especially oncogenesis. MDSCs can suppress both adaptive and innate immunities through multiple mechanisms. However, most of our knowledge of MDSCs is based on pre-clinical studies. Clinical observations have shown that the number of MDSCs in the peripheral blood of patients is closely related to tumor stage, tumor burden, remote metastasis and prognosis, though inconsistencies in MDSC phenotypes among cancer patients mean that results have been inconclusive, and subsequent research progress has been slow. This review summarizes recent studies that have investigated MDSCs in cancer patients.