Renal damage during type II cryoglobulinemia

THE CONTEXT: Type II cryoglobulinemia, composed of a monoclonal IgM rheumatoid factor directed against polyclonal IgG, is associated in most cases with chronic hepatitis C viral infection. THE CHARACTERISTICS OF RENAL DAMAGE: Frequent, the renal damage usually occurs after the onset of various systemic manifestations and is expressed by moderate renal failure, microscopic haematuria, proteinuria lower than 3 g/d and hypertension difficult to control. More severe aspects are possible such as acute nephrotic or nephritic syndromes, or even multi-organ failure with anuria. A renal biopsy confirms the diagnosis by revealing a membranoproliferative glomerulonephritis, characterized by the intensity of the monocyte infiltration and glomerular deposits, often arranged in curved microtubules under electronic microscopy and often associated with vasculitis lesions. Progression towards terminal renal failure is rare. THERAPEUTIC MODALITIES: Treatment, unclearly defined, relies on anti-virals (interferon a and ribavirin), which are partially effective when the viral replication is inhibited, associated with corticosteroids and immunosuppressors or even plasma exchange in the severe forms. The management and treatment of the cardiovascular complications condition the vital prognosis.     

Renal damage during type I cryoglobulinemia

CHARACTERISTICS OF THE RENAL DAMAGE: Type I cryoglobulinemia, composed of a single monoclonal immunoglobulin, may be responsible for a glomerulopathy with clinical presentation and histological characteristics close to those of mixed cryoglobulinemia. CONTEXT: Type I cryoglobulins complicate a malignant haematological disease, chronic lymphoid leukaemia or non-Hodgkin's malignant lymphoma in 60% of cases. EVOLUTION: Treatment with corticosteroids and immunosuppressors or antimitotics often leads to the parallel stabilisation or remission of the renal manifestations and the haematological disease     

AT1 receptors and the actin cytoskeleton during angiotensin II treatment

BACKGROUND: The response of proximal convoluted tubules (PCTs) to angiotensin II is mediated by specific type 1 receptors found on both apical and basolateral surface membrane cells. After ligand association with type 1 receptors, different signaling pathways are triggered and determine changes in fluid absorption (Jv). The presence of AT1 and actin cytoskeleton, which are directly related to Jv, can undergo changes in distribution based on the actions of AngII and losartan. METHODS: Using a microperfusion technique and immunohistochemistry analysis, we investigated the basolateral action in PCTs, of AngII and/or losartan on Jv in rabbits, with regard to AT1 and actin cytoskeleton. RESULTS: AngII increased Jv, while in contrast, losartan and combined AngII + losartan led to its decrease. AngII did not change fluorescence intensity of AT1 receptors on tubular membranes, while losartan and AngII + losartan demonstrated a slight increase after treatment. On the other hand, AngII increased the fluorescence intensity of actin cytoskeleton, while losartan induced a decrease. AngII + losartan led actin cytoskeleton having a higher fluorescence intensity than in the control group. CONCLUSIONS: In the present study, we demonstrated that treatment of the basolateral side of PCT cells with AngII and losartan could lead to changes in absorptive tubular function. Important alterations were detected in AT1 receptor fluorescence on the luminal and basolateral membranes, and changes in F-actin cytoskeleton were verified by fluorescence following these protocols.     

Renal hemodynamic effect of angiotensin II type 2 receptor

In the present study, the role of the angiotensin II type 2 receptor in the regulation of medullary blood flow in conscious Spontaneous Hypertensive Rats(SHR) was investigated. We tested the hypothesis that AT2 receptor activation may exert the opposite effects of AT1 receptors in terms of renal hemodynamics. Mean arterial pressure(MAP), daily sodium balance, cortical blood flow(CBF), and medullary blood flow(MBF) were measured over a 10-day protocol in several groups of rats in which optical fibers for laser-Doppler flowmetry had been implanted and which received the following drug combinations: the AT1 receptor antagonist CV11976(CV) alone and CV plus AT2 receptor antagonist PD123319 (PD). In the CV alone group, the renal interstitial administration of CV decreased MAP, caused sodium diuresis, and increased MBF significantly. In the CV plus PD group, the renal interstitial administration of PD prevented sustained hypotension, sodium diuresis, and increased medullary blood flow during CV administration. These data indicated that AT2 receptor activation leads to vasodilation in the renal medulla and an antihypertensive effect in SHR. AT2 receptors play an important role in the renal medullary blood flow.     

Renal AT 1 receptors and hypertension.

Arterial hypertension participates actively in the developmentand progression of cardiovascular risk (CVR). The kidney playsa double role of culprit in the development of arterial hypertensionand victim, when it suffers the consequences of persistentlyelevated blood pressure. On the other hand, it has been clearlydemonstrated that as soon as the kidney is damaged by arterialhypertension, there is a concomitant rise in global CVR thataccounts for an enhanced prevalence of fatal and non-fatal cardiovascularevents currently observed in patients with chronic kidney disease     

Deficiency of intrarenal angiotensin II type 2 receptor impairs paired homeo box-2 and N-myc expression during nephrogenesis

We previously demonstrated that angiotensin II (Ang II) stimulates paired homeo box-2 (Pax-2) via the Ang II type 2 receptor (AT(2)R). The Pax-2 gene and N-myc play pivotal roles in renal morphogenesis via their effects on cell proliferation and differentiation in embryonic mesenchymal cells and embryonic mouse kidneys. Since AT(2)R knock-out (KO) mice have a phenotype that is similar to that of humans with congenital renal and urinary tract anomalies (CAKUT) and develop hypertension in adulthood, these mice and wild-type controls were used for this study. Embryonic kidneys isolated from E12 to term gestation were cultured in Dulbecco's modified Eagle's medium (DMEM) with or without Ang II (10(-6) M) for 24 h ex vivo. Renal morphogenesis was histologically assessed. Mean glomerular tuft volume was determined by the method of Weibel and Gomez with the aid of image analysis software. Pax-2 and N-myc gene expression were determined by immunostaining as well as by Western blotting and real-time-quantitative polymerase chain reaction (RT-qPCR). Glomerular size was significantly smaller, and Pax-2 and N-myc expression down-regulated, in kidneys of AT(2)R KO mice compared with those of wild-type mice. In ex vivo studies, Ang II stimulated Pax-2 and N-myc mRNA expression in embryonic kidneys of wild-type mice, but this stimulatory effect was absent in embryonic kidneys of AT(2)R KO mice. Taken together, these data indicate that intrarenal AT(2)R plays an important role in nephrogenesis. Deficiency of AT(2)R may impair both Pax-2 and N-myc expression, eventually resulting in glomerular hyperfiltration that may, ultimately, lead to later development of hypertension.     

Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors.

Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in (3)H-glucosamine/(35)S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and G alpha i/o-mediated mechanisms in the effects of the two receptors.     

Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance

The renin-angiotensin system with its active metabolite angiotensin (Ang) II has been related not only to hypertension but also to obesity and insulin resistance. Recent evidence obtained in vitro suggests that the type 2 Ang II receptor (AT2R) mediates the trophic action of Ang II on adipocyte differentiation and lipogenesis. We used AT2R(y/-) mice to delineate a potential role of AT2R in adipose tissue development and metabolism. AT2R(y/-) mice had a normal adiposity but displayed a striking adipose tissue phenotype characterized by small adipocytes and an increase in cell number. In muscle, the expression of several genes involved in lipid metabolism, including fatty acid translocase, uncoupling protein-3, peroxisome proliferator-activated receptors (alpha, delta), and carnitine palmitoyl transferase-1, was increased in AT2R-deficient mice. In response to high-fat feeding, these mice were protected against obesity and obesity-related glucose intolerance, as assessed by glucose tolerance tests. Moreover, lipid oxidation assessed by indirect calorimetry was higher in AT2R-deficient mice than in wild-type mice, irrespective of the diet. This suggests that AT2R-dependent signaling exerts a direct or indirect negative control on lipid utilization in muscles. These data support the idea that AT2R-dependent Ang II signaling increases adipose cell mass and glucose intolerance and thus could participate to the deleterious effects of a high-fat diet.     

Renal sensitivity to angiotensin II in type 1 diabetes

The role of the renin angiotensin system for the regulation of kidney function in diabetes mellitus is uncertain. Results from studies in diabetic animals suggest that a reduced activity in this system contributes to the renal hyperperfusion and hyperfiltration in diabetes. The renal sensitivity to angiotensin II in diabetic patients is also unknown. Changes in renal hemodynamics were measured after infusion of two low doses of angiotensin II in ten young type 1 diabetic patients without complications and in ten healthy controls. The renin and angiotensin II levels were found to be the same in both groups. The baseline glomerular filtration rate was higher in the diabetics. During the highest angiotensin II dose, the 51Cr-EDTA and PAH clearance decreased 14 +/- 15 and 157 +/- 118 ml/min in the diabetics and 14 +/- 15 and 146 +/- 109 in the controls respectively. The changes in blood pressure and renal vascular resistance or sodium excretion did not differ between the groups. A malfunction of the renin angiotensin system is thus unlikely as a cause of the glomerular hyperfiltration in type 1 diabetes.     

Renal responses to AT1 blockade in angiotensin II-induced hypertensive rats.

Previous studies have shown that uninephrectomized rats infused chronically with low doses of angiotensin II (Ang II) develop progressive hypertension that is prevented by coadministration of losartan in the drinking water. The present study was performed to contrast the effects of chronic and acute losartan treatment in reversing the Ang II-mediated actions on arterial pressure and renal function. Ang II was infused subcutaneously via osmotic minipumps (40 ng/min) for 13 days in two groups (N = 10 and N = 6); one group also received losartan in the drinking water (30 mg/kg.day) throughout this period. Untreated rats (N = 6) and rats (N = 6) receiving only losartan served as control groups. Ang II-infused rats had higher mean arterial pressures (153 +/- 7 versus 107 +/- 3 mm Hg) and lower GFR (0.7 +/- 0.04 versus 0.98 +/- 0.06 mL/min.g) than Ang II-infused rats receiving losartan chronically. The Ang II-infused rats responded to acute doses of losartan (10 mg/kg) with progressive reductions in arterial pressure and significant increases in cortical blood flow (34 +/- 12% increase), renal plasma flow, GFR, and sodium excretion; however, the increases in renal blood flow and GFR were not sustained as systemic arterial pressure decreased. Because Ang II-infused rats receiving losartan chronically still exhibited decreases in RBF in response to a bolus dose of Ang II, further studies evaluated the effects of acute losartan treatment in rats treated chronically with losartan. Although arterial pressure decreased only slightly, demonstrating adequate systemic vascular blockade, there were still substantial and sustained increases in renal plasma flow, cortical blood flow (20 +/- 4% increase), GFR, and sodium excretion. In summary, the modest responses to acute losartan in Ang II-infused rats indicate that chronic Ang II infusions lead to alterations in renal function that are only partially reversible by acute losartan treatment. In contrast, chronic treatment with losartan prevents the Ang II-induced decrease in GFR. The renal responses to acute losartan in the Ang II-infused rats treated chronically with losartan suggest that substantive intrarenal actions of Ang II can be maintained even when the systemic vascular AT1 receptors are effectively blocked.     

Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers

Aggressive treatment of hypertension is effective in reducing both microvascular and macrovascular complications in type 2 diabetes, and target BP less than 130/85 or 130/80 mmHg are now recommended. Inhibition of renin angiotensin aldosterone system (RAAS) plays an essential role in the treatment of hypertension and diabetes-related complications. Studies focusing on renal end-points suggest that angiotensin-converting enzyme inhibitors (ACE-I) are more effective than other traditional agents in reducing the onset of clinical proteinuria in both type 1 and type 2 diabetic patients with incipient nephropathy, mainly in normotensive ones (secondary prevention). However, several small trials in type 2 diabetic patients with overt nephropathy (tertiary prevention) failed to demonstrate a specific renoprotective role for ACE-I, at variance with type 1 diabetes. Three recent large trials address the question of whether angiotensin II receptor blockers (ARB) prevent the development of clinical proteinuria or delay the progression of nephropathy in type 2 diabetes. The IRMA study showed that irbesartan is more effective than conventional therapy in preventing the development of clinical proteinuria and in favoring the regression to normoalbuminuria for comparable BP control in patients with incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more effective than traditional antihypertensive therapies in reducing progression toward end-stage renal failure (ESRF) in type 2 diabetic patients with overt nephropathy independently of changes in BP. Moreover, a reduction in hospitalizations for heart failure was demonstrated for ARB-treated patients compared with placebo. Furthermore, the LIFE study showed that losartan is more effective than conventional therapy in reducing cardiovascular morbidity and mortality in a cohort of diabetic patients with hypertension and left ventricular hypertrophy. In conclusion, ARB seem to be effective in both preventing renal damage and reducing progression toward ESRF in type 2 diabetic patients. Thus, the guidelines for the prevention and treatment of diabetic nephropathy are now changed. In type 1 diabetes ACE-I are the first-choice drug; in type 2 diabetes, ARB are considered first-choice drugs in secondary prevention as well as ACE-I and have been now elected the unique first-choice drug in tertiary prevention of ESRF. Finally, ARB should be considered as the first-choice drug in cardiovascular prevention too, as well as ACE-I.     

Different role of angiotensin II type 1 and type 2 receptors in renin release by interaction of angiotensin II and renal sympathetic nerve

Background. Angiotensin II (Ang II) is involved in the direct inhibition of renin release from juxtaglomerular (JG) cells in the kidney as the negative feedback loop of the renin-angiotensin system. Ang II also modulates renin release via the sympathetic nervous system, since the renal sympathetic nerves stimulate renin release, and the interaction of the sympathetic nervous system with Ang II has been demonstrated to occur at multiple levels. Methods. Experiments were performed in conscious unrestrained rabbits. Ang II (1.0 ng/kg per min) was infused intravenously for 60 min in renal-denervated (Dx; n = 6) and sham-denervated (Sh; n = 6) rabbits, and plasma renin activity (PRA) was determined. Then the intrarenal administration of the Ang II type-1 receptor (AT1R) antagonist, losartan, or type-2 receptor (AT2R) antagonist, PD123319 was carried out, during infusion of Ang II or saline in both Dx and Sh. Results. PRA was decreased in both Sh (5.9 ± 0.6 to 2.8 ± 0.7 ng/ml per h; n = 6, P < 0.01) and Dx (5.7 ± 0.4 to 3.8 ± 0.6 ng/ml per h; n = 6, P < 0.01) during Ang II infusion. The degree of decrease was significantly less in Dx than in Sh (P < 0.05), indicating that the inhibition of renin release by Ang II is associated with renal nerves. The intrarenal administration of losartan in Sh significantly decreased PRA produced by Ang II (5.6 ± 0.3 to 4.8 ± 0.3 ng/ml per h; n = 6, P < 0.05) vs. saline vehicle (5.7 ± 0.3 to 2.8 ± 0.2 ng/ml per h; n = 6, P < 0.01) (P < 0.05). Blockade with losartan in Dx significantly increased PRA (5.8 ± 0.4 to 6.6 ± 0.4 ng/ml per h; n = 6, P < 0.05) during the infusion of Ang II. Renin response to the Ang II infusion was not influenced by the intrarenal administration of PD123319 alone, in either Sh or Dx. Conclusion. Ang II appears to facilitate sympathetic neurotransmission through the postjunctional AT1R leading to renin release. Received: August 12, 1998 / Accepted: October 9, 1998     

Renal carcinosarcoma (mixed tumours) of the kidney

Two cases of renal carcinosarcoma are reported. The classification and pathogenesis of these tumours are discussed, and their gross and microscopic features providing diagnostic clues are described.     

Renal angiotensin converting enzyme (ACE) expression in diabetic rats: the effect of ACE inhibitors]

Renal excreted angiotensin converting enzyme (ACE) inhibitor captopril, and renal.hepatic bile excreted ACE inhibitor temocapril, were compared by monitoring serum ACE and renal ACE expression (protein and mRNA) in streptozotocin-induced diabetic rats. Serum ACE levels did not change in untreated diabetic rats or in those treated with temocapril, compared with normal control rats. However, serum ACE levels significantly increased in diabetic rats treated with captopril after 3 months (153.8 +/- 23.0 vs. 43.5 +/- 5.5 IU/l/37 degrees C, p < 0.01) and 6 months (113.6 +/- 9.3 vs. 36.9 +/- 2.9 IU/l/37 degrees C, p < 0.01) compared with normal control rats. Compared with normal control rats (3.6 +/- 0.4), proximal tubular ACE protein expression significantly (p < 0.01) decreased in untreated diabetic rats (1.6 +/- 1.1), but significantly (p < 0.01) increased in diabetic rats treated with captopril (3.7 +/- 0.3) and temocapril (3.5 +/- 0.4). Renal ACE mRNA levels decreased in untreated diabetic rats (125.5 +/- 20.3 vs. 313.3 +/- 53.4, p < 0.01) compared with normal control rats for 6 months. Renal ACE mRNA levels tended to increase in diabetic rats treated with captopril (184.4 +/- 51.2 vs. 125.5 +/- 20.3) and temocapril (165.4 +/- 43.2 vs. 125.5 +/- 20.3) compared with untreated diabetic rats for 6 months. In conclusion, diabetic rats had lower proximal tubular ACE protein expression and lower renal ACE mRNA levels compared with normal control rats. Furthermore, both ACE inhibitors increased renal ACE protein and mRNA expression, but differed in their effect on serum ACE levels.     

内皮素受体阻断剂对糖尿病大鼠肾脏血管紧张素Ⅱ1型受体表达的影响

目的：观察糖尿病大鼠肾脏血管紧张素Ⅱ1型（AT1）受体的改变以及内皮素受体阻断剂bosentan对其影响。方法：将SD大鼠建成链脲佐菌素诱导的糖尿病模型,设非治疗组、bosentan治疗组和正常对照组。4周后采用免疫组织化学、Western blot及RT－PCR方法检测肾脏AT1受体基因和蛋白表达。结果：与SD对照组相比,糖尿病大鼠存在明显的蛋白尿和内生肌酐清除率升高,其肾脏AngⅡ水平明显升高,同时伴有AT1受体的mRNA和蛋白表达显著下降。bosentan能显著缓解上述异常。结论：糖尿病大鼠肾脏AngⅡ及AT1受体表达明显异常,bosentan具有治疗作用。     

Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of alpha-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.     

Increased angiotensin-converting enzyme and type 1 angiotensin receptors in cortical vasculature and tubulointerstitium of chronically rejected human kidney allografts

SUMMARY: Chronic rejection of human renal allografts after transplantation is characterized by interstitial infiltration, arteriosclerosis and glomerulosclerosis in the grafts. Apart from tissue HLA compatibility, angiotensin II (AII) may be implicated in accelerating the processes of chronic rejection. In the present study, the cellular distribution of angiotensin‐converting enzyme (ACE) and type 1 AII (AT₁) receptors was mapped and compared in non‐rejected human kidneys (n = 8) and chronically rejected renal allografts (n = 9) using complementary immunohistochemistry and quantitative in vitro autoradiography. Chronically rejected allografts showed typical histopathological characteristics of tissue rejection, including concentric intimal thickening of intrarenal arteries, extensive or focal glomerulosclerosis, tubular atrophy and severe tubulointerstitial fibrosis. In rejected allografts, total ACE binding in the cortex was decreased to 46% of that in non‐rejected kidneys (P < 0.01), whereas AT₁ receptor binding in the glomeruli and the inner stripe of the outer medulla was maintained. However, ACE and AT₁ receptor binding were increased in the cortical tubulointerstitium of chronically rejected allografts. In non‐rejected kidneys, strong ACE immunostaining occurred in proximal tubules and vascular endothelium, whereas AT₁ receptors occurred in vascular smooth muscle cells, as expected. In rejected allografts, intense ACE and AT₁ receptor immunostaining were detected not only in the same sites as those non‐rejected kidneys, but also in cortical tubulointerstitium between atrophied tubules and surrounding the glomeruli. AT₁ receptors were markedly up‐regulated in vascular smooth muscle cells of thickened atherosclerotic vessels. These results provide novel morphological evidence that increased expression and/or altered distribution of ACE and AT₁ receptors in cortical tubulointerstitium and in the neointima of intrarenal arteries may play an important role in the progression of chronic rejection of human renal allografts after transplantation.