Hypertension: Franco M

Rosas M, Pastelín G, Vargas-Alarcón G, Martínez-Reding J, Lomelí C, Mendoza-González C, Lorenzo JA, Méndez A, Franco M, Sánchez-Lozada LG, Verdejo J, Sánchez N, Ruiz R, Férez-Santander SM, Attie F, Anonymous00054. · Departamento de Cardiología Adultos III, Instituto Nacional de Cardiología "Ignacio Chávez", Tlalpan, México DF. · Arch Cardiol Mex. · Pubmed #18928127 No free full text.

Abstract: The multidisciplinary Institutional Committee of experts in Systemic Arterial Hypertension from the National Institute of Cardiology "Ignacio Chávez" presents its update (2008) of "Guidelines and Recommendations" for the early detection, control, treatment and prevention of Hypertension. The boarding tries to be simple and realistic for all that physicians whom have to face the hypertensive population in their clinical practice. The information is based in the most recent scientific evidence. These guides are principally directed to hypertensive population of emergent countries like Mexico. It is emphasized preventive health measures, the importance of the no pharmacological actions, such as good nutrition, exercise and changes in life style, (which ideally it must begin from very early ages). "We suggest that the changes in the style of life must be vigorous, continuous and systematized, with a real reinforcing by part of all the organisms related to the health education for all population (federal and private social organisms). It is the most important way to confront and prevent this pandemic of chronic diseases". In this new edition the authors amplifies the information and importance on the matter. The preventive cardiology must contribute in multidisciplinary entailment. Based mainly on national data and the international scientific publications, we developed our own system of classification and risk stratification for the carrying people with hypertension, Called HTM (Arterial Hypertension in Mexico) index. Its principal of purpose this index is to keep in mind that the current approach of hypertension must be always multidisciplinary. The institutional committee of experts reviewed with rigorous methodology under the principles of the evidence-based medicine, both, national and international medical literature, with the purpose of adapting the concepts and guidelines for a better control and treatment of hypertension in Mexico. This work group recognizes that hypertension is not an isolated disease; therefore its approach must be in the context of the prevalence and interaction with other cardiovascular risk factors such as obesity, diabetes, dislipidemia and smoking among others. The urgent necessity is emphasized to approach in a concatenated form the diverse cardiovascular risk factors, since independently of which they share common pathophysiological mechanisms, its suitable identification and control will affect without any doubt the natural history of the other concatenated risk factor. By all means that to greater participation of factors, greater it will be the global cardiovascular risk but never, however, the specific weight is due to avoid that each one has on the global cardiovascular risk. In this Second edition we try to amplify and give systematic forms for the clinical approach for the suspicion of secondary hypertension and we emphasizes that hypertension in the woman with or without menopause should be careful analyzed, and special recommendations are given for the hypertension in pregnancy. Also we have approached some aspects related to the hypertensive emergencies and other special situations. In this second version some recommendations are presented for boarding hypertension in children and adolescents.

Franco M, Sanchez-Lozada LG, Bautista R, Johnson RJ, Rodriguez-Iturbe B. · Department of Nephrology, Instituto Nacional de Cardiología I. Ch., Juan Badiano No.1, Mexico City, Mexico. · Blood Purif. · Pubmed #18182795 No free full text.

Abstract: It has been recognized for many years that salt intake is one of the main environmental factors responsible for the development of hypertension. More than 30 years ago, Guyton and co-workers postulated a relationship between blood pressure and natriuresis which maintains sodium balance and extracellular volume; thus an impaired ability of the kidney to excrete sodium requires an increase in blood pressure to increase natriuresis and correct the sodium balance, resulting in hypertension. Currently, the mechanisms responsible for the alterations mentioned above remain under investigation. Among them, microvascular and tubulointerstitial injury induce salt retention and development of salt-sensitive hypertension that appears to be mediated in part by lymphocytes and macrophages infiltrating the tubulointerstitium that produce angiotensin II and stimulate oxidative stress. In the post-angiotensin salt-sensitive hypertension model, angiotensin levels are elevated despite systemic angiotensin II levels being suppressed, and the local angiotensin II levels correlate with the presence of intrarenal inflammation and cortical vasoconstriction. Under these conditions, blockade of the angiotensin II AT1 receptors ameliorate cortical vasoconstriction. Thus, the renal angiotensin system in association with interstitial immune infiltrating cells may play a pivotal role in the development and maintenance of salt-sensitive hypertension.

Sánchez-Lozada LG, Nakagawa T, Kang DH, Feig DI, Franco M, Johnson RJ, Herrera-Acosta J. · Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico. · Curr Opin Nephrol Hypertens. · Pubmed #16340663 No free full text.

Abstract: PURPOSE OF REVIEW: Current evidence supports the role of soluble uric acid as a true mediator of injury, exerting its effects through the induction of growth factors, cytokines, hormones and autacoids. In the present review, we summarize recent studies on the mechanisms involved in the uric acid deleterious effects. RECENT FINDINGS: Although uric acid is considered an antioxidant in plasma, recent clinical and epidemiological studies have found that hyperuricemia is associated with mortality and development of hypertension, cardiovascular and chronic renal diseases. Experimental studies suggest that uric acid induce its detrimental effects at the cellular level entering to vascular smooth muscle cells (VSMC) via an organic anion transport system, and followed by the activation of specific MAP kinases, nuclear transcription factors, with stimulation of COX-2, PDGF A and C chain, PDGF alpha receptor, and various inflammatory mediators, including C-reactive protein and monocyte chemoattractant protein-1. Physiologically, these effects translate into a rise of arterial pressure, VSMC hypertrophy, tubulointerstitial infiltration and glomerular hypertension in the setting of renal vasoconstriction. Uric acid also promotes endothelial dysfunction through inactivation of NO and arresting the proliferation of endothelial cells. Thus, arteriosclerosis induced by hyperuricemia may be a novel mechanism for the development of essential hypertension. SUMMARY: Soluble uric acid has important biologic roles. While it acts as an antioxidant, there is also evidence that uric acid has pro-inflammatory and proliferative effects on VSMC, and causes dysfunction of endothelial cells. These cellular mechanisms may translate into why uric acid is associated with renal and cardiovascular disease.

Tapia E, Sánchez-González DJ, Medina-Campos ON, Soto V, Avila-Casado C, Martínez-Martínez CM, Johnson RJ, Rodríguez-Iturbe B, Pedraza-Chaverrí J, Franco M, Sánchez-Lozada LG. · Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Juan Badiano 1, 14080 Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #18753301 No free full text.

Abstract: We evaluated whether the blockade of the proinflammatory transcription factor NF-kappaB would modify the oxidative stress, inflammation, and structural and hemodynamic alterations found in the kidney as a result of massive proteinuria. Twenty male Sprague-Dawley rats were injected with 2 g of BSA intraperitoneally daily for 2 wk. Ten of them received in addition the inhibitor of NF-kappaB activation pyrrolidine dithiocarbamate (PDTC; 200 mg.kg(-1).day(-1) sc) and the rest received vehicle. Seven rats that received intraperitoneal saline were used as controls. Glomerular hemodynamics were studied after 14 days. Markers of oxidative stress (NF-kappaB subunit p65+ cells, 3-nitrotyrosine, and 4-hydroxynonenal), inflammation (cortical CD68+ cells and NOS-II), and afferent arteriole damage were assessed by immunohistochemistry and morphometry. Activity of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase was evaluated in renal cortex and medulla. Albumin overload induced massive proteinuria, oxidative stress with reduced activity of antioxidant enzymes, NF-kappaB activation, inflammatory cell infiltration, a significant presence of proteinaceous casts, systemic and glomerular hypertension, as well as arteriolar remodeling. Treatment with PDTC prevented or improved all of these findings. In this model of nephrotic syndrome, we demonstrate a key role for oxidative stress and inflammation in causing systemic and glomerular hypertension and proteinuria. Oxidative stress and inflammation may have a key role in accelerating renal injury associated with intense proteinuria.

Sánchez-Lozada LG, Soto V, Tapia E, Avila-Casado C, Sautin YY, Nakagawa T, Franco M, Rodríguez-Iturbe B, Johnson RJ. · Department of Nephrology, INC Ignacio Chávez, Juan Badiano 1. 14080. Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #18701632 No free full text.

Abstract: Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.

Sánchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Wessale JL, Zhao L, Johnson RJ. · Department of Nephrology, INC Ignacio Chavez, Mexico City, Mexico. · Nephron Physiol. · Pubmed #18434753 No free full text.

Abstract: BACKGROUND/AIMS: The effect of febuxostat (Fx), a non-purine and selective xanthine oxidase inhibitor, on glomerular microcirculatory changes in 5/6 nephrectomy (5/6 Nx) Wistar rats with and without oxonic acid (OA)-induced hyperuricemia was evaluated. METHODS: Four groups were studied: 5/6 Nx+vehicle (V)+placebo (P) (n = 7); 5/6 Nx+V+Fx (n = 8); 5/6 Nx+OA+P (n = 6) and 5/6 Nx+OA+Fx (n = 10). OA (750 mg/kg/day, oral gavage) and Fx (3-4 mg/kg/day, drinking water) were administered for 4 weeks. Systolic blood pressure, proteinuria and plasma uric acid were measured at baseline and at the end of 4 weeks. Measurement of glomerular hemodynamics and evaluation of histology were performed at the end of 4 weeks. RESULTS: 5/6 Nx+OA+P rats developed hyperuricemia, renal vasoconstriction and glomerular hypertension in association with further aggravation of afferent arteriolopathy compared to 5/6 Nx+V+P. Fx prevented hyperuricemia in 5/6 Nx+OA+Fx rats and ameliorated proteinuria, preserved renal function and prevented glomerular hypertension in both 5/6 Nx+V+Fx and 5/6 Nx+OA+Fx groups. Functional improvement was accompanied by preservation of afferent arteriolar morphology and reduced tubulointerstitial fibrosis. CONCLUSION: Fx prevented renal injury in 5/6 Nx rats with and without coexisting hyperuricemia. Because Fx helped to preserve preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension.

Sánchez-Lozada LG, Tapia E, Bautista-García P, Soto V, Avila-Casado C, Vega-Campos IP, Nakagawa T, Zhao L, Franco M, Johnson RJ. · Dept. of Nephrology, Instituto Nacional de Cardiología Ignacio Chavez, Juan Badiano 1, 14080 Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #18216151 links to  free full text

Abstract: Increased fructose consumption is associated with hyperuricemia, metabolic syndrome, and renal damage. This study evaluated whether febuxostat (Fx), an investigational nonpurine, and selective xanthine oxidase inhibitor, could alleviate the features of metabolic syndrome as well as the renal hemodynamic alterations and afferent arteriolopathy induced by a high-fructose diet in rats. Two groups of rats were fed a high-fructose diet (60% fructose) for 8 wk, and two groups received a normal diet. For each diet, one group was treated with Fx (5-6 mg.kg(-1).day(-1) in the drinking water) during the last 4 wk (i.e., after the onset of metabolic syndrome), and the other received no treatment (placebo; P). Body weight was measured daily. Systolic blood pressure and fasting plasma uric acid (UA), insulin, and triglycerides were measured at baseline and at 4 and 8 wk. Renal hemodynamics and histomorphology were evaluated at the end of the study. A high-fructose diet was associated with hyperuricemia, hypertension, as well as increased plasma triglycerides and insulin. Compared with fructose+P, fructose+Fx rats showed significantly lowered blood pressure, UA, triglycerides, and insulin (P < 0.05 for all comparisons). Moreover, fructose+Fx rats had significantly reduced glomerular pressure, renal vasoconstriction, and afferent arteriolar area relative to fructose+P rats. Fx treatment in rats on a normal diet had no significant effects. In conclusion, normalization of plasma UA with Fx in rats with metabolic syndrome alleviated both metabolic and glomerular hemodynamic and morphological alterations. These results provide further evidence for a pathogenic role of hyperuricemia in fructose-mediated metabolic syndrome.

Sánchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M, Zhao L, Johnson RJ. · Department of Nephrology, Instituto Nacional de Cardiologiá Ignacio Chavez, Juan Badiano 1, 14080-Mexico City, Mexico. · Nephrol Dial Transplant. · Pubmed #18048425 No free full text.

Abstract: BACKGROUND: Experimentally-induced hyperuricaemia [due to inhibition of uricase with oxonic acid (OA)] in rats causes hypertension and renal alterations which can be prevented by lowering uric acid (UA) with allopurinol. Febuxostat (Fx), an investigational, nonpurine and selective xanthine oxidase inhibitor, is a more effective UA-lowering agent than allopurinol. We therefore tested the hypothesis that Fx might be useful in treating hyperuricemia-induced hypertension and renal damage. METHODS: Four groups of male rats were studied: OA (750 mg/kg by daily gavage) was given for 8 weeks and Fx (5-6 mg/kg/day in drinking water; OA+Fx: n = 10) or placebo (OA+P: n = 11) were administered for 4 weeks beginning at 4 weeks after initiation of the study. Two groups of normal (N) rats were studied as controls (N+P and N+Fx: n = 10/group). Systolic blood pressure (SBP) and fasting plasma UA were measured in all animals at baseline and at 4 and 8 weeks. Glomerular haemodynamics by micropuncture techniques were determined at 8 weeks followed by histological evaluation of glomerular and afferent arteriole morphologies. RESULTS: In OA-induced hyperuricaemic rats, Fx lowered UA and ameliorated systemic and glomerular hypertension as well as mesangial matrix expansion and the development of preglomerular arteriolar disease as indicated by a reduction of the arteriolar area and media-to-lumen ratio. In normal rats, Fx tended to lower UA and had no effect on blood pressure, renal hemodynamics and afferent arteriole morphology. CONCLUSION: These results suggest that Fx merits further evaluation for the treatment of hypertension and renal alterations induced by hyperuricaemia.

Franco M, Bautista R, Pérez-Méndez O, González L, Pacheco U, Sánchez-Lozada LG, Santamaría J, Tapia E, Monreal R, Martínez F. · Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #17942570 links to  free full text

Abstract: Since marked renal vasoconstriction is observed in angiotensin II (ANG II)-mediated hypertensive rats, we studied the possible interaction between ANG II and adenosine in this model. ANG II was infused into male Wistar rats through osmotic minipumps (435 ng x kg(-1) x min(-1)) for 14 days. In sham and ANG II groups, renal tissue and interstitial adenosine were measured; both increased to a similar twofold extent in the ANG II-treated rats (31.40 +/- 4 vs. 62.0 +/- 8.4 nM, sham vs. ANG II, interstitial adenosine; P< 0.001). The latter decreased by 47% with the specific blockade of 5'-nucleotidase. Glomerular hemodynamics demonstrated marked renal vasoconstriction in the angiotensin-treated group, which was reverted by an adenosine A(1)-receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, 10 mug.kg(-1) x min(-1)). 5'-Nucleotidase and adenosine deaminase (ADA) activities were measured in the cytosolic and membrane fractions. Only the membrane ADA activity decreased from 1,202 +/- 80 to 900 +/- 50 mU/mg protein in the ANG II-treated rats (P< 0.05), as well as in their protein and mRNA expression. Despite the adenosine elevation, A(1) and A(2b) receptor protein did not change; in contrast, downregulation was observed in A(2a) receptor and upregulation in A(3) receptor. A similar pattern was found in the cortex and in the medulla; mRNA significantly decreased only in the A(3) receptor in both segments. These results suggest that the elevation of renal tissue and interstitial adenosine contributes to the renal vasoconstriction observed in the ANG II-induced hypertension and that it is mediated by a decrease in the activity and expression of ADA, increased production of adenosine, and an induced imbalance in adenosine receptors.

Simões do Espírito Santo K, Teixeira Vde P, Costa Hde O, Franco M. · Department of Pathology, Paulista School of Medicine of Federal University of São Paulo, Brazil. · Int J Surg Pathol. · Pubmed #17478782 No free full text.

Abstract: Adult polycystic kidney disease (APKD) is a common and potentially fatal disease, leading to end-stage renal failure in 50% of cases. The disease is frequently complicated by arterial hypertension, bacterial pyelonephritis, and hematuria. The association between APKD and tuberculosis has rarely been reported and is related to a more unfavorable course since the infection becomes refractory to specific treatment. The authors report 2 cases of renal tuberculosis diagnosed in the native nephrectomy specimens of 2 patients with APKD after renal transplantation. Tuberculosis, although not common, must be recognized as a potential source of infection of native polycystic kidneys in immunocompromised transplant recipients.

Franco M, Martínez F, Quiroz Y, Galicia O, Bautista R, Johnson RJ, Rodríguez-Iturbe B. · Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico. · Am J Physiol Regul Integr Comp Physiol. · Pubmed #17475676 No free full text.

Abstract: Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with (n = 10) and without (n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- (n = 7) and normal (n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean +/- SD) low plasma (2.4 +/- 1.4 pg/ml) and high interstitial AII concentration (1,310 +/- 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 +/- 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

Gallo AP, Silva LB, Franco M, Burdmann EA, Bueno V. · FAMERP São José do Rio Preto Medical School, Av.Brig.Faria Lima, 5416, Rua Francisco Giglioti, 160 ap 71, São Jose do Rio Preto, SP 15090-000, Brazil. · Int Immunopharmacol. · Pubmed #17219691 No free full text.

Abstract: Calcineurin inhibitors (CNIs) are routinely used in immunosuppressive therapy and both Cyclosporine (CsA) and Tacrolimus (FK506) show similar efficacies to prevent rejection and death within the first year after organ transplantation. However, their use is limited by side effects such as kidney damage, hypertension, onset of diabetes and hyperlipidemia. It is a consensus that compared with CsA, FK506 causes less changes in blood pressures, serum lipids and renal function. Nevertheless, FK506 use is associated with a higher incidence of post-transplant diabetes mellitus (PTDM). FTY720 is a new compound that has shown a protective effect in animal models with respect to rejection in transplantation, ischemia-reperfusion injury, autoimmune diseases and tumor development. FTY720 acts by altering lymphocytes homing from blood to peripheral lymphoid organs. In mice, FTY720 administered in combination with CsA during 21 days has prolonged skin allograft survival without causing significant renal changes. In a model of CsA-induced chronic nephropathy in rats, FTY720 administration prevented renal injury suggesting benefit from using a combination of these drugs. In a canine kidney allograft model, FTY720 in combination with low doses of CsA or FK506 showed an addictive anti-rejection effect without causing critical adverse effects. We therefore, investigated whether 21 days of FTY720 administration in association with FK506 could prevent renal damage and development of diabetes in mice. Mice receiving FK506 alone or FTY720 + FK506 during 21 days showed changes in kidney function and structure besides an increase in blood glucose and lymphopenia. The FTY720 + FK506 combination requires further investigation with an aim toward understanding the mechanisms involved with respect to side effects.

Sánchez-Lozada LG, Tapia E, López-Molina R, Nepomuceno T, Soto V, Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M. · Dept. of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1. 14080, Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #17190912 links to  free full text

Abstract: 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.

Sánchez-Lozada LG, Tapia E, Jiménez A, Bautista P, Cristóbal M, Nepomuceno T, Soto V, Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M. · Dept. of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1. 14080, Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #16940562 links to  free full text

Abstract: 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<F10<F60). In addition, the F60 rats developed kidney hypertrophy, glomerular hypertension, cortical vasoconstriction, and arteriolopathy of preglomerular vessels. In conclusion, fructose-induced metabolic syndrome is associated with renal disturbances characterized by renal hypertrophy, arteriolopathy, glomerular hypertension, and cortical vasoconstriction. These changes are best observed in rats administered high doses (60% diet) of fructose.

Bautista-García P, Sánchez-Lozada LG, Cristóbal-García M, Tapia E, Soto V, Avila-Casado MC, Márquez-Velasco R, Bojalil R, Franco M, Herrera-Acosta J. · Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, 14080-Mexico City, Mexico. · Nephrol Dial Transplant. · Pubmed #16935907 links to  free full text

Abstract: 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.

Franco M, Martínez F, Rodríguez-Iturbe B, Johnson RJ, Santamaría J, Montoya A, Nepomuceno T, Bautista R, Tapia E, Herrera-Acosta J. · Department of Nephrology, Instituto Nacional de Cardiología I Ch, Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #16868307 links to  free full text

Abstract: 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.

Tapia E, Franco M, Sánchez-Lozada LG, Soto V, Avila-Casado C, Santamaría J, Quiroz Y, Rodríguez-Iturbe B, Herrera-Acosta J. · Departments of Nephrology and Pathology, Instituto Nacional de Cardiología "Ignacio Chávez," México City, México. · Kidney Int. · Pubmed #12631080 No free full text.

Abstract: BACKGROUND: Although renal protective effect of interrupting the inflammatory process is well established, it is still controversial if it also prevents the glomerular hemodynamic disturbances that initiate renal injury. We investigated the effects of suppressing inflammation with mycophenolate mofetil (MMF) on glomerular hemodynamics, arteriolar structural changes, and renal histologic injury in rats with subtotal renal ablation METHODS: Micropuncture studies were performed 30 days after 5/6 nephrectomy in rats untreated and treated with MMF (30 mg/kg/day). Renal histology, immunohistochemistry for lymphocytes, macrophages and inducible nitric oxide synthase (iNOS) expression, as well as afferent arteriolar (AA) morphometry was evaluated. RESULTS: Renal ablation significantly increased proteinuria (6.8 to 82.7 mg/day), mean arterial pressure (MAP) (120 to 166 mm Hg), single-nephron glomerular filtration rate (SNGFR) (34.8 to 56.3 nL/min), glomerular plasma flow (QA) (117.7 to 246.9 nL/min), and glomerular capillary pressure (PGC) (48.9 to 61.0 mm Hg). Afferent resistance (AR), efferent resistance, and ultrafiltration coefficient remained unchanged. Despite persisting arterial hypertension (152 mm Hg), MMF prevented proteinuria (13.3 mg/day), and significantly reduced SNGFR (44.4 nL/min), PGC (49.1 mm Hg), and QA (163.2 nL/min) due to a rise in AR (3.13 vs. 2.18 1010 dyn/sec/cm-5). Glomerular sclerosis, tubulointerstitial damage, lymphocyte and macrophage infiltration, and iNOS expression were significantly reduced by MMF, in addition hypertrophy of AA resistance evaluated by the media/lumen ratio was prevented (P < 0.001). CONCLUSIONS: Reduction in proteinuria, SNGFR, QA, and PGC, despite elevated MAP, indicate preservation of AA function. These results suggest that inflammation associated arteriolopathy of AA contributes to glomerular hemodynamic disturbances that participate in the progression of renal disease.

de Lezo JS, Medina A, Romero M, Pan M, Segura J, Caballero E, Pavlovic D, Ortega JR, Franco M, Delgado A, Ojeda S, Mesa D, Lafuente M. · Hospital Reina Sofía, University of Córdoba, Córdoba, Spain. · Am Heart J. · Pubmed #12422159 No free full text.

Abstract: BACKGROUND: Adult patients with atrial septal defect (ASD) and pulmonary hypertension have a more advanced degree of disease, frequently having functional class deterioration and atrial arrhythmias when they are aged >40 years. Surgery at this age prolongs life expectancy and limits functional deterioration. Although percutaneous ASD device occlusion is an accepted alternative to surgery, there is limited information on the immediate and long-term effects of device occlusion in middle-aged and elderly patients with ASD and pulmonary hypertension. METHODS: From a total of 101 patients with secundum ASD who were receiving treatment with percutaneous device occlusion, we selected for analysis 29 adult patients (mean age 56 +/- 14 years) with a baseline peak pulmonary pressure of >40 mm Hg (mean 65 +/- 23 mm Hg). Three of the patients had suprasystemic pulmonary pressure and a bidirectional shunt. Six patients were asymptomatic at treatment. The remaining 23 had different degrees of dyspnea; 14 of them had an advanced New York Heart Association functional class (III-IV). Twelve patients had chronic atrial fibrillation. At cardiac catheterization, the mean ratio of pulmonary to systemic flow was 1.8 +/- 0.5, and the pulmonary-to-systemic pressure ratio was 0.66 +/- 0.22. The mean diameter of the defect, as evaluated by the stretching balloon method, was 26 +/- 7 mm. All patients received an Amplatzer septal occluder (Golden Valley, Minn). Seven patients had combined therapeutic procedures for associated anomalies before the implant: mitral balloon valvuloplasty (n = 1), stent coronary revascularization (n = 1), stent in pulmonary vein stenosis (n = 1), and internal catheter defibrillation (n = 4). After treatment, patients were followed up by clinical and echocardiographic Doppler studies every 6 months. RESULTS: Immediately after the implantation, the peak systolic pulmonary pressure significantly decreased to 54 +/- 21 mm Hg (P <.001). A clear improvement in functional status was observed after the treatment in all symptomatic patients, especially in those with refractory heart failure. There were no major complications. Six patients who had atrial fibrillation at baseline study recovered to a stable sinus rhythm after treatment, and it was maintained at discharge. Complete ASD occlusion by echocardiographic Doppler at discharge was observed in 28 patients (97%). After a mean follow up of 21 +/- 14 months, clinical improvement persisted in all previously symptomatic patients, and the peak systolic pulmonary pressure, obtained by echocardiographic Doppler, further decreased to 31 +/- 11 mm Hg (P <.001) compared with baseline and immediately after hemodynamic measurements. CONCLUSIONS: Our findings suggest that percutaneous device occlusion of ASD in adult patients with pulmonary hypertension is safe and effective and provides significant and prolonged relief.

Sánchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaría J, Nakagawa T, Rodríguez-Iturbe B, Johnson RJ, Herrera-Acosta J. · Department of Nephrology, Instituto Nacional de Cardiologia I Chavez, 14080 Mexico City, Mexico. · Am J Physiol Renal Physiol. · Pubmed #12372787 links to  free full text

Abstract: Mildly hyperuricemic rats develop renin-dependent hypertension and interstitial renal disease. Hyperuricemia might also induce changes in glomerular hemodynamics. Micropuncture experiments under deep anesthesia were performed in Sprague-Dawley rats fed a low-salt diet (LS group), fed a low-salt diet and treated with oxonic acid (OA/LS group), and fed a low-salt diet and treated with oxonic acid + allopurinol (OA/LS/AP group) for 5 wk. The OA/LS group developed hyperuricemia and hypertension compared with the LS group: 3.1 +/- 0.2 vs. 1.1 +/- 0.2 mg/dl (P < 0.01) and 143 +/- 4 vs. 126 +/- 2 mmHg (P < 0.01). Hyperuricemic rats developed increased glomerular capillary pressure compared with the LS rats: 56.7 +/- 1.2 vs. 51.9 +/- 1.4 mmHg (P < 0.05). Pre- and postglomerular resistances were not increased. Histology showed afferent arteriolar thickening with increased alpha-smooth muscle actin staining of the media. Allopurinol prevented hyperuricemia (1.14 +/- 0.2 mg/dl), systemic (121.8 +/- 2.8 mmHg) and glomerular hypertension (50.1 +/- 0.8 mmHg), and arteriolopathy in oxonic acid-treated rats. Linear regression analysis showed that glomerular capillary pressure and arteriolar thickening correlated positively with serum uric acid and systolic blood pressure. Glomerular hypertension may be partially mediated by an abnormal vascular response to systemic hypertension due to arteriolopathy of the afferent arteriole.

Herrera-Acosta J, Tapia E, Sánchez-Lozada LG, Franco M, Striker LJ, Striker GE, Rodríguez IB. · Instituto Nacional de Cardiología, Departamento de Nefrología, Juan Badiano 1-Tlapan 1, D.F. 4080-1408 Mexico, D.F., México. · J Hypertens Suppl. · Pubmed #12184053 No free full text.

Abstract: To study whether prevention of renal injury using the anti-inflammatory drugs pentosan polysulphate (PPS) and mycophenolate mofetil (MMF) is associated with improvement of glomerular haemodynamics, PPS and MMF were compared with losartan. The awake systolic blood pressure (SBP), proteinuria (Uprot) and micropuncture studies were performed 30 days after five-sixths nephrectomy in untreated rats and in rats treated with PPS (100 mg/kg per day), MMF (30 mg/kg per day) or losartan (30 mg/kg per day). In the rats receiving no treatment, there was a rise in SBP (to 180-200 mmHg) and in Uprot, which were prevented by losartan. In the PPS and MMF groups, the SBP was elevated but the Uprot did not increase. In the untreated rats the total glomerular filtration rate (GFR) decreased (-80%) and the single-nephron GFR (37-42%), plasma flow (67-127%) and glomerular pressure (10-15 mmHg) increased. These changes were prevented by PPS and MMF to the same extent as by losartan: the rise in single-nephron GFR and plasma flow were reduced by 50% and the glomerular pressure was normal. In rats receiving losartan, this was due to the fall in arterial pressure, whereas in PPS- and MMF-treated rats it was due to a rise in afferent resistance, indicating autoregulatory capacity. Total GFR was similar, despite the lower single-nephron GFR in treated groups, suggesting a larger proportion of functioning nephrons. Losartan, PPS and MMF significantly reduced glomerular sclerosis and tubular dilation and atrophy in association with a reduction in the lymphocyte and macrophage infiltrate. These results suggest an interaction between the haemodynamic and inflammatory changes that perpetuate each other during progression of renal injury. Renal protection provided by anti-inflammatory drugs is partially mediated by the prevention of glomerular haemodynamic alterations.

Franco M, Tapia E, Santamaría J, Zafra I, García-Torres R, Gordon KL, Pons H, Rodríguez-Iturbe B, Johnson RJ, Herrera-Acosta J. · Department of Nephrology, Instituto Nacional de Cardiología, Mexico City, Mexico. · J Am Soc Nephrol. · Pubmed #11675402 links to  free full text

Abstract: Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 +/- 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 +/- 8.2 mmHg at week 1 and 163 +/- 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 +/- 2.3 mmHg at week 1 and 148 +/- 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.