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Biomedical subjects

Jaime Herrera-Acosta

Publications and source records attributed to Jaime Herrera-Acosta.

At least 19 recordsLinked to original sources
PubMed2005

A unifying pathway for essential hypertension.

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.

Animals↗
PubMed2005

Hemodynamics of hyperuricemia.

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.

Animals↗
PubMed2005

Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats.

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.

Animals↗
PubMed2004

Proteinuria in rats induced by serum from patients with collapsing glomerulopathy.

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.

Adolescent↗
PubMed2004

Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all.

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.

Humans↗
PubMed2003

Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Animals↗
PubMed2003

Familial collapsing glomerulopathy: clinical, pathological and immunogenetic features.

BACKGROUND: Collapsing glomerulopathy (CG) is an aggressive form of glomerular injury frequently seen in association with HIV infection, although it is also recognized in non-HIV patients as a primary disease. Until now, the occurrence of CG in a familial pattern has not been reported. METHODS: We studied five members of a family (siblings), admitted for evaluation of proteinuria and nephrotic syndrome. They had no other family history of renal disease. Blood samples for major histocompatibility complex (MHC) analysis were obtained from the five siblings, both parents and four relatives. RESULTS: Renal biopsy performed in four out of the five siblings revealed capillary collapse and retraction with visceral epithelial cell swelling and reabsorption droplets, consistent with CG. Two of the patients had suggestive symptoms of systemic lupus erythematosus, such as arthritis, rash, hair loss, moderate leukopenia and lymphopenia, low titers of antinuclear antibodies (ANA) and anti-SSA/Ro antibodies, but no immune complex deposition on renal biopsy. IgG serology for parvovirus B19 (PVB-19) was positive only in two siblings but polymerase chain reaction (PCR) was negative. Immunogenetic analysis showed that all patients shared the same MHC haplotype inherited from the mother. CONCLUSIONS: CG can present in a familial pattern. Since a similar MHC haplotype was observed in affected and non-affected members of the family, we conclude that the environment plays an important role in the development of the disease.

Adolescent↗
PubMed2003

Mycophenolate mofetil prevents arteriolopathy and renal injury in subtotal ablation despite persistent hypertension.

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.

Animals↗
PubMed2003

Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation.

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.

Albuminuria↗
PubMed2003

Apoptosis and NFkappaB activation are simultaneously induced in renal tubulointerstitium in experimental hypertension.

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

Angiotensin II↗
PubMed2003

Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition.

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.

Angiotensin II↗
PubMed2003

Tubulointerstitial disease: role of ischemia and microvascular disease.

PURPOSE OF REVIEW: Tubulointerstitial injury is characteristic of aging-associated renal injury and progressive renal disease. Salt-sensitive hypertension is also associated with tubulointerstitial inflammation, especially when accompanied by microvascular disease. Here we summarize recent studies on the pathogenesis and consequences of tubulointerstitial disease, emphasizing the role of ischemia and the microvasculature. RECENT FINDINGS: Tubulointerstitial injury occurs via several mechanisms of which one of the most important is chronic ischemia. Recent studies suggest that chronic vasoconstriction may contribute to the renal injury associated with angiotensin II, catecholamines, nitric oxide inhibition, hypokalemia, hyperuricemia, and cyclosporine nephropathy. Salt-sensitivity may result as a consequence of the tubulointerstitial inflammatory response to these conditions, and this appears to be perpetuated by the development of preglomerular vascular disease. With progression of tubulointerstitial disease there is also a loss of peritubular capillaries, and stimulating microvascular growth with angiogenic factors can stabilize renal function in these models. SUMMARY: Ischemia secondary to vasoconstriction or to structural changes of the renal vasculature may have important consequences both in terms of mediating salt-sensitive hypertension and renal progression. Angiogenic factors may have potential benefit in preventing or treating these conditions.

Animals↗