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Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure. Background. Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion. Methods. Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks. Results. MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 ± 30 Ang II-positive cells/mm2 at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified. Conclusions. SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN. [ABSTRACT FROM AUTHOR]

Background: Extensive renal ablation is associated with progressive sclerosis of the remnant kidney. Because lymphocytes and monocytes accumulate in the remnant kidney, it is likely that they play a role in the renal scarring. Therefore, we treated rats with 5/6 nephrectomy (5/6Nx) with mycophenolate mofetil (MMF), a drug that has an antiproliferative effect and that suppresses the expression of intercellular adhesion molecules.Methods: Sprague-Dawley rats with 5/6Nx received MMF (30 mg. kg-1. day-1 by daily gastric gavage, N = 15) or vehicle (N = 16). Ten additional rats were sham operated. All rats were fed a 30% protein diet. Body weight, serum creatinine, and urinary protein excretion were determined weekly. Lipid peroxidation, as a measure of oxidative stress observed by urinary malondialdehyde determinations, was performed every two weeks. Histologic studies were done in the remnant kidney four weeks (9 rats from the vehicle-treated group, 7 rats from the MMF group, and 5 sham-operated rats) and eight weeks after surgery (the remaining rats). Glomerular volume, sclerosis in glomeruli (segmental and global) and interstitium (semiquantitative scale), infiltrating lymphocytes and macrophages (CD43- and ED1-positive cells), and expression of adhesion molecules (CD54, CD18, and CD11b) were analyzed.Results: MMF treatment prevented the progressive increment in serum creatinine and the proteinuria observed in the 5/6 nephrectomized rats during the eight weeks of observation (P < 0.01). Weight gain was comparable in the MMF-treated and sham-operated rats, whereas weight gain was decreased in untreated 5/6 nephrectomized rats. Excretion of malondialdehyde increased after surgery but returned sooner to control levels in the MMF-treated rats. Increments in glomerular size and mean arterial blood pressure induced by renal ablation were not modified by MMF treatment. Eight weeks after surgery, segmental sclerosis was present in 48.4 +/- 8.35% (+/- sd) glomeruli in the vehicle-treated group versus 25 +/- 10.5% in the MMF-treated group (P < 0.001). Interstitial fibrosis was reduced significantly with MMF treatment (P < 0.001). Infiltration with CD43- and ED1-positive cells in glomeruli and interstitium was two to five times lower in MMF-treated rats (P < 0.01). Expression of adhesion molecules CD18 and CD11b was similarly reduced.Conclusion: MMF ameliorates the progressive renal damage in the remnant kidney after 5/6Nx. This effect is associated with a reduction in the infiltration of lymphocytes and monocytes, whereas glomerular hypertrophy and systemic hypertension are unchanged. [ABSTRACT FROM AUTHOR]

Experimental hyperuricemia (HU) results in preglomerular arteriolopathy, cortical vasoconstriction, and glomerular hypertension. Recently, uric acid has been shown to induce endothelial dysfunction. We therefore studied the effect of acute and chronic administration of l-arginine (a substrate for endothelial nitric oxide synthase) on the renal hemodynamic and vascular structural alterations induced by HU. To induce HU, oxonic acid (OA; 750 mg.kg(-1).day(-1)) was administered in male Sprague-Dawley rats. To study the acute effect of arginine, nine rats received l-arginine (l-Arg; 15 mg.kg(-1).min(-1)) during micropuncture. To elucidate the chronic effect of l-Arg, OA + 1% l-Arg (n = 8) and OA + 2.5% l-Arg (n = 6; drinking water) were evaluated throughout the 5-wk period. Eight normal control (N), and eight OA, rats were also studied. Kidneys were fixed by perfusion and afferent arteriole morphology was evaluated. HU rats developed the renal functional and structural alterations described and had suppressed urinary excretion of NO(2)(-)/NO(3)(-). Acute stimulation of nitric oxide (NO) synthesis markedly increased urinary NO(2)(-)/NO(3)(-), lowered systemic blood pressure, and relieved cortical vasoconstriction despite a significant increment of glomerular hypertension and afferent arteriole damage. Increasing doses of chronic l-Arg were associated with increasing excretion of urinary NO(2)(-)/NO(3)(-), reduction of systemic hypertension, and prevention of cortical vasoconstriction (2.5% l-Arg). In addition, both doses prevented glomerular hypertension and preglomerular arteriolopathy. Thus an acute relief of renal vasoconstriction in the setting of afferent arteriole damage cannot reverse glomerular hypertension, likely due to impairment in preglomerular autoregulation. On the other hand, chronic l-Arg preserved arteriolar structures probably mediated by the antiproliferative effect of NO on vascular smooth muscle cells.

Fructose intake has been recently linked to the epidemic of metabolic syndrome and, in turn, the metabolic syndrome has been epidemiologically linked with renal progression. The renal hemodynamic effects of fructose intake are unknown, as well as the effects of different routes of administration. Metabolic syndrome was induced in rats over 8 wk by either a high-fructose diet (60%, F60, n = 7) or by adding fructose to drinking water (10%, F10, n = 7). Body weight and food and fluid intake of each rat were measured weekly during the follow-up. At baseline and at the end of wk 8, systolic blood pressure, plasma uric acid, and triglycerides were measured. At the end of week 8 glomerular hemodynamics was evaluated by micropuncture techniques. Wall thickening in outer cortical and juxtamedullary afferent arterioles was assessed by immunohistochemistry and computer image analysis. Fructose administration either in diet or drinking water induced hypertension, hyperuricemia, and hypertriglyceridemia; however, there was a progressive increment in these parameters with higher fructose intake (C

Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 +/- 1.3 lymphocytes/mm2, and 30.8 +/- 1.2 macrophages/mm2 ANG II vs. 19.6 +/- 2 lymphocytes/mm2, and 22 +/- 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 +/- 74.6 pg/ml ANG II vs. 194 +/- 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 +/- 0.9 lymphocytes/mm2 and 15.9 +/- 0.8 machophages/mm2), ANG II levels (436.9 +/- 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

Background: Chronic renal damage is associated with inflammatory infiltration, fibrosis and vascular lesion, coupled with increased expression of cyclo-oxygenase 2 (COX-2) and transforming growth factor-beta1 (TGF-beta1). However, the role of inducible nitric oxide synthase (NOS-2) is still controversial. Thus, we studied the contribution of NOS-2 to the expression levels of COX-2 and TGF-beta1, as well as the structural renal injury in rats with subtotal renal ablation (5/6 Nx)., Methods: Four groups of rats were studied: sham, 5/6 Nx, 5/6 Nx+aminoguanidine (AG) and 5/6 NX+L-NIL (L-N6-iminoethyl-lysine). Systolic blood pressure (SBP), proteinuria and creatinine (Cr) clearance were measured. NOS-2, COX-2 and TGF-beta1 gene expression was determined by real-time reverse transcription-polymerase-chain reaction. Protein expression was evaluated by western blot and ELISA (TGF-beta1). Immunohistochemistry and morphometry were performed for NOS-2, microvascular thickening and fibrosis., Results: Systemic hypertension and marked proteinuria, increased expression of NOS-2, COX-2 and TGF-beta1, thickening of arteriolar wall and tubulointerstitial fibrosis were produced in 5/6 Nx rats. Chronic inhibition of NOS-2 did not prevent arterial hypertension or the fall in Cr clearance, but partially reduced proteinuria. Nevertheless, AG and L-NIL preserved arteriolar morphology and the administration of both selective inhibitors of inducible NOS (AG and L-NIL) prevented NOS-2 overexpression., Conclusion: This study shows that NOS-2 was markedly enhanced in renal tissue of 5/6 Nx rats. Moreover, treatment with AG and L-NIL prevented the morpho-functional changes induced by subtotal renal ablation, despite persistence of systemic hypertension, suggesting that high concentrations of nitric oxide produced by NOS-2 could act as a positive modulator of the proinflammatory and profibrotic pathways involved in the progression of renal disease.

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

Uric acid might often be regarded as a simple marker of renal disease. Although it is well known that hyperuricemia causes gout which is associated with renal insufficiency and cardiovascular disease, one might think that it could attribute to the intrarenal urate crystal, but not to uric acid per se. In order to clarify the role of uric acid in the kidney, we hypothesized that uric acid causes renal disease. To generate mild hyperuricemia without intrarenal crystal in rats, we used low doses of an uricase inhibitor (2% oxonic acid). Hyperuricemia induced systemic hypertension, glomerular hypertrophy/hypertension, afferent arteriolar sclerosis, and macrophage infiltration in normal rat kidney. In progressive renal disease, such as cyclosporine nephropathy and remnant kidney in rat, uric acid accelerated the progression of renal disease. Thus, we concluded that uric acid is not a simple marker, but a cause of renal disease., (Copyright 2006 S. Karger AG, Basel.)

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.

Background: A number of cross-sectional or serial studies have demonstrated the clinical impact of microproteinuria and macroproteinuria by identifying individuals at risk of both end-stage renal disease and major cardiovascular events. This study focused on the prevalence of proteinuria in Mexico and its relationship with other cardiovascular risk factors such as hypertension, type 2 diabetes mellitus, body mass index, smoking, age, and gender., Methods: The prevalence of proteinuria in Mexico was obtained from the probabilistic cross-sectional national health survey performed in the year 2000. The proportion of urine dipstick samples that tested positive for protein (defined as > or =1+) in adults from 20 to 69 years of age was determined. The analysis was performed using both algebraic and multicategorical models. Potential interactions between proteinuria and other major cardiovascular risk factors were investigated., Results: A total of 46,523 adult survey participants were included in the analysis. In the general population, 9.2% had proteinuria. By univariate, multivariate, and multicategorical analysis, hypertension, diabetes, obesity, and age were strongly associated with the prevalence of proteinuria (P < 0.001). However, in Mexico, the specific distribution of age groups demonstrated that the absolute number of patients without hypertension that had proteinuria is not irrelevant. To identify 1 case of proteinuria, one would need to screen 3 persons with diabetes mellitus, 5 patients with hypertension without diabetes, or 6 persons over the age of 55 years. When proteinuria is present, the probability of having a noncommunicable chronic disease or other major cardiovascular risk factor is more than 85%., Conclusion: Proteinuria is prevalent. When considered together, dipstick-positive proteinuria, blood pressure level, body mass index > or =30 m(2)/kg, and abnormal fasting blood glucose measured on a single occasion identifies different segments of the population. Studies such as this may be a suitable initial clinical approach to general population screening for renal and cardiovascular risk stratification.

We present the hypothesis that most cases of essential hypertension occur via two phases. The first phase is initiated by episodes of renal vasoconstriction induced by a hyperactive sympathetic nervous system, activation of the renin-angiotensin system, or hyperuricemia resulting from diet or genetics. During this phase the hypertension is salt resistant and renin dependent, and the kidney normal. Over time, preglomerular vascular disease develops (arteriolosclerosis), associated with tubulointerstitial inflammation; this shifts the hypertension to a salt-sensitive, volume-dependent, and renal-dependent pathway. This pathway unites many of the previous hypotheses on the etiology of hypertension, and offers insights into ways to prevent, ameliorate, or cure the underlying process.

Prolonged hyperuricemia is associated with the development of hypertension, renal arteriolosclerosis, glomerulosclerosis, and tubulointerstitial injury. It confers a greater risk than proteinuria for developing chronic renal disease and is associated with the development of hypertension. Mild chronic hyperuricemia without intrarenal crystal deposition was induced in rats by inhibiting uricase with oxonic acid. Hyperuricemic rats developed hypertension, afferent arteriolar thickening, and mild renal interstitial fibrosis. Additionally, hyperuricemia accelerated renal damage and vascular disease in rats undergoing renal ablation. To better understand the role of hyperuricemia in the kidney, micropuncture studies were performed. Hyperuricemia resulted in renal cortical vasoconstriction (single nephron glomerular filtration rate (SNGFR) 35%, P < .05) and glomerular hypertension (P < .05). The possibility that hyperuricemia could modify renal hemodynamic disturbances during progression of renal disease was tested in rats with 5/6 nephrectomy. Hyperuricemia accentuated the renal vascular damage and caused cortical vasoconstriction (SNGFR 40%, P < .05) and persistent glomerular hypertension. In conclusion, hyperuricemia impairs the autoregulatory response of preglomerular vessels, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening results in severe vasoconstriction. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis as well as arterial hypertension.

Background: Hyperuricemia has been associated with renal disease. Because glomerular hemodynamic alterations critically contribute to initiation and progression of renal disease, we evaluated the effect of mild hyperuricemia in glomerular microcirculatory changes in rats under normal conditions and with renal injury induced by subtotal renal ablation (RK)., Methods: Hyperuricemia was induced in normal and remnant kidney (RK) rats on a normal sodium diet by administration of oxonic acid (OA). To prevent hyperuricemia, allopurinol (AP) was administered concomitantly. Glomerular hemodynamics were evaluated by micropuncture techniques. Systolic blood pressure (SBP), proteinuria, arterial morphology, and serum uric acid were measured. In RK rats, glomerulosclerosis, fibrosis, and inflammatory cell infiltration (CD5+) were also assessed., Results: In normal rats, hyperuricemia resulted in afferent arteriole thickening associated with renal cortical vasoconstriction [single nephron glomerular filtration rate (SNGFR) -35%, P < 0.05) and glomerular hypertension (P < 0.05). Allopurinol treatment prevented structural and functional alterations. In RK rats, hyperuricemia produced more renal vascular damage than control animals coupled with severe cortical vasoconstriction (SNGFR -40%, P < 0.05) and persistent glomerular hypertension. Allopurinol partially prevented cortical vasoconstriction, and fully prevented arteriolopathy and glomerular hypertension associated with significantly less infiltration of CD5+ cells., Conclusion: Hyperuricemia induces arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis, as well as arterial hypertension. These studies provide a potential mechanism by which hyperuricemia can mediate hypertension and renal disease.

Objective: Based on a National Re-survey on Hypertension (HTA) and other cardiovascular risk factors performed in Mexico during 2003 and 2004 in the adult population with HTA, as identified in the 2000 National Survey of Health, this study was planed to determine: 1) morbidity and mortality rates; 2) the incidence and interrelation with other risk factors, such as overweight, obesity, dyslipidemia, nephropathy and diabetes; 3) the main risk factors associated to HTA involved in its complications, need for hospitalization and number of days; and, 4) the degree of therapeutical adhesion and the type of antihypertensive drugs used., Methods: The survey was of type III using the step by step method described by WHO. Sampling was weighed a priori taking into account a national prevalence average of HTA of 30.05% and its corresponding rate for each federal state. Permissible maximum error in the estimation = 0.28. Effect of design = 4.5; and, Rate of awaited answer (0.70)., Results: From the initial 14,567 interviewed patients, 1,165 (8%) subjects were considered non-hypertensive or false positives at the 2000 survey. From the 13,402 remaining patients, 335 died during the first 2 years of pursuit, which implies an annual mortality of approximately 1.15% in the hypertensive population. Thus, 13,067 survivors were subjected to the final analysis. The mean age at the re-survey was 45.6 +/- 12.6; 40.5% were men (n = 5,295). There was a statistically significant difference in height, but not in weight between both genders. The control HTA was raised 14.6% in the year 2000 and 19.2% in 2004. The prevalence of diabetes was duplicated from 16% to 30% (< .001). Fifty four percent of the whole population required hospitalization at least once during the period of study. The rates of overweight, obesity, and dyslipidemia rose significantly (p < 0.05) independently from age, federal state, and gender., Conclusion: RENAHTA shows the impact of hypertension on the morbidity and mortality during the 3.1 +/- 1.5 years of follow-up in Mexico. It alerts us on the need to reinforce the strategies of attention and prevention of this crucial risk factor and of screening the dynamic nonlinear interaction between the main cardiovascular risk factors in Mexico. New hypotheses are proposed for the metabolic syndrome.

Background: Primary collapsing glomerulopathy recurs postransplant, raising the possibility of circulating factors implicated in the pathogenesis of the disease., Methods: To determine the presence of circulating factors in collapsing glomerulopathy patients, we tested serum from those patients in an in vivo assay. Eleven groups of rats received serum from collapsing glomerulopathy patients, idiopathic focal segmental glomerulosclerosis (FSGS) or healthy subjects in its native form, isolated IgG, or serum without IgG. The presence of proteinuria and creatinine clearance were determined. Histopathologic analysis included light, immunofluorescence, and electron microscopy., Results: Collapsing glomerulopathy rats developed proteinuria while rats injected with serum from FSGS and healthy subjects did not. Rats injected with serum of collapsing glomerulopathy in its native form developed marked proteinuria (99.2 +/- 42 mg/24 hours at day 5, P= 0.0001, compared to the baseline), and decreased in creatinine clearance. Rats receiving isolated IgG or serum without IgG from collapsing glomerulopathy developed mild proteinuria (46.5 +/- 8.4 mg/24 hours and 30.9 +/- 11 mg/24 hours, respectively, at day 5 (P= 0.0001). Glomerular tuft retraction and podocyte damage were seen only in collapsing glomerulapthy rats. No abnormalities were found in rats injected with serum from FSGS or healthy subjects., Conclusion: Circulating factors in the serum of collapsing glomerulopathy patients produce podocyte damage, whereas such factors are not present in noncollapsing FSGS. IgG eluates from collapsing glomerulopathy produce proteinuria when injected into the rat. Such factors remain in the circulation when serum of patients is adsorbed into protein A, raising the possibility that there are more than one circulating factor present in patients with collapsing glomerulopathy.

Recent evidence indicates that interstitial infiltration of T cells and macrophages plays a role in the pathogenesis of salt-sensitive hypertension. The present review examines this evidence and summarizes the investigations linking the renal accumulation of immune cells and oxidative stress in the development of hypertension. The mechanisms involved in the hypertensive effects of oxidant stress and tubulointerstitial inflammation, in particular intrarenal ANG II activity, are discussed, focusing on their potential for sodium retention. The possibility of autoimmune reactivity in hypertension is raised in the light of the proinflammatory and immunogenic pathways stimulated by the interrelationship between oxidant stress and inflammatory response. Finally, we present some clinical considerations derived from the recognition of this interrelationship.

Background: Oxidative stress is known to induce apoptosis and activation of pro-inflammatory transcription factor nuclear factor kappa B (NFkappaB), which are biologic effects that may play a role in the renal damage associated with arterial hypertension. We investigated if increased apoptosis and NFkappaB activation were present in experimental models of hypertension., Methods: Sprague-Dawley rats fed with regular rodent chow and free access to water were studied. The Ang II group (N = 6) received 435 ng/kg/min of angiotensin II during 2 weeks by subcutaneous minipumps. The l-NAME group (N = 5) received Nomega-nitro-l-arginine-methyl-ester (l-NAME) in the drinking water (70 mg/100 mL) for 3 weeks. The control group consisted of 6 rats. Systolic blood pressure (tail cuff plethysmography), serum creatinine, and proteinuria were determined weekly. Kidneys were examined for superoxide-positive cells (histochemistry) and for apoptosis [terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labeling (TUNEL)-positive cells], proliferation [proliferating cell nuclear antigen (PCNA)-positive cells), and activation of NFkappaB (p65 subunit) with the appropriate antibodies., Results: As expected, hypertension developed in experimental groups. Tubulointerstitial superoxide-positive cells were increased 7 times (P < 0.001), TUNEL-positive cells were increased 3 to 4 times (P < 0.001), PCNA-positive cells were increased 20 to 30 times (P < 0.001), and NFkappaB activation was increased 4 to 5 times (P < 0.001) in the experimental groups. NFkappaB expression correlated with the number of interstitial lymphocytes (r = 0.667, P < 0.01) and macrophages (r = 0.835, P < 0.001)., Conclusion: Angiotensin II infusion and l-NAME administration induce oxidative stress and increased apoptosis and activation of the transcription factor NFkappaB. These effects may participate in the development of progressive renal injury resulting from uncontrolled hypertension

Glomerular hemodynamic adaptations to loss of renal mass are thought to be the initiating factor of progression to renal failure; however, tubulointerstitial (TI) injury correlates better with progression than with glomerular damage. Thus, it is conceivable that tubulointerstitial alterations participate in the pathophysiology of renal disease progression by modifying the adaptive responses of glomerular hemodynamics. In experimental models of progressive renal disease, suppressing tubulointerstitial inflammatory cell infiltration with anti-inflammatory drugs reduces renal damage despite persistence of systemic hypertension. In recent studies in rats with subtotal renal ablation, we found that treatment with polysulphate pentosan (PPS) and with mycophenolate mofetil (MMF) prevented proteinuria, glomerular hypertension, and hyperfiltration, despite persisting arterial hypertension due to higher afferent resistance. In addition, arteriolopathy was significantly attenuated by MMF, suggesting preservation of vascular structure and function. Association of vascular injury of afferent arterioles, glomerular hemodynamic changes, and renal lesions has been described in other conditions such as hyperuricemia, protein overload, fawn-hooded rats, and aging spontaneously hypertensive rats (SHR). Arteriolopathy results in a maladaptive function that permits the transmission of systemic hypertension to glomerular capillaries. Glomerular hypertension results in mechanical damage to the capillary wall and increased filtration of proteins to tubular lumen. Enhanced tubular reabsorption induces synthesis of proinflammatory and profibrotic factors, resulting in tubulointerstitial inflammation and fibrosis. In conditions in which there is overactivity of the renin-angiotensin system (RAS), such as mild hyperuricemia and protein overload, arteriolopathy is associated with increased glomerular pressure and reduced glomerular plasma flow that results in post-glomerular ischemia and tubulointerstitial injury.

Background: Angiotensin II (Ang II) infusion and nitric oxide synthesis (NOS) inhibition with Nomega-nitro-l-arginine-methyl-ester (l-NAME) are experimental models of hypertension associated with renal inflammation and oxidative stress. To gain insight into the nature of the tubulointerstitial injury induced in these models, we studied lectin-binding specificities, vimentin expression, and heat shock protein (HSP) 60 and 70 in these experimental models., Methods: Sprague-Dawley rats received Ang II infusion (435 ng/kg/min) for 2 weeks by subcutaneous minipumps (Ang II group, N = 5) or l-NAME in the drinking water (70 mg/100 mL) for 3 weeks (l-NAME group N = 7). The control group consisted of 10 rats. Systolic blood pressure (tail-cuff plethysmography), serum creatinine, and proteinuria were determined weekly. At the end of the treatment period, rats were sacrificed and kidneys studied. Binding specificities of fluorescein-labeled lectins were examined in frozen sections, and cellular infiltrates were identified by immunohistology and expression of vimentin and HSP 60 and 70 with immunohistochemistry and computer image analysis., Results: Tubulointerstitial accumulation of macrophages, lymphocytes, and Ang II-positive cells were present in the Ang II group and l-NAME group. Vimentin, HSP 60, and HSP 70 were increased 8 to 20 times in the cortex of the rats of the Ang II group and the l-NAME groups. Neoexpression of vimentin and HSPs was found primarily in proximal tubular cells., Conclusion: Ang II infusion and NOS inhibition induce tubular injury with epithelial cell transdifferentiation and expression of stress proteins. The role of these changes in the accumulation and activation of the interstitial inflammatory infiltrate merits further investigation.