Biomedical subjects

R J Johnson

Publications and source records attributed to R J Johnson.

At least 37 records · Page 2Linked to original sources

PubMed2001

Intranet-based quality improvement documentation at the Veterans Affairs Maryland Health Care System.

The Pathology and Laboratory Medicine Service of the Veterans Affairs Maryland Health Care System is inspected biannually by the College of American Pathologists (CAP). As of the year 2000, all documentation in the Anatomic Pathology Section is available to all staff through the VA Intranet. Signed, supporting paper documents are on file in the office of the department chair. For the year 2000 CAP inspection, inspectors conducted their document review by use of these Web-based documents, in which each CAP question had a hyperlink to the corresponding section of the procedure manual. Thus inspectors were able to locate the documents relevant to each question quickly and efficiently. The procedure manuals consist of 87 procedures for surgical pathology, 52 procedures for cytopathology, and 25 procedures for autopsy pathology. Each CAP question requiring documentation had from one to three hyperlinks to the corresponding section of the procedure manual. Intranet documentation allows for easier sharing among decentralized institutions and for centralized updates of the laboratory documentation. These documents can be upgraded to allow for multimedia presentations, including text search for key words, hyperlinks to other documents, and images, audio, and video. Use of Web-based documents can improve the efficiency of the inspection process.

Databases, Factual↗

PubMed2001

Analysis of CD34+ cell subsets in stem cell harvests can more reliably predict rapidity and durability of engraftment than total CD34+ cell dose, but steady state levels do not correlate with bone marrow reserve.

In peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells transplanted has been shown to correlate well with both rapidity and durability of engraftment. However, it is clear that engraftment does not necessarily correlate with total CD34+ cell numbers in some patients. Consequently, there is increasing interest in evaluating the role of CD34+ subsets in haemopoietic recovery as a more accurate marker of harvest quality. We analysed the numbers of CD34+ cell subsets, namely Thy-1+, L-Selectin+ and CD38-, and correlated this with engraftment in 86 patients undergoing PBSCT. Adequate engraftment was defined as being a platelet count greater than 50 x 10(9)/l and a neutrophil count greater than 1.0 x 10(9)/l. CD34+L-Selectin+ provided the best prediction of engraftment rapidity, although the improvement over total CD34+ cell dose was minor. Only the dose of CD34+Thy-1+ cells transplanted correlated with durable engraftment. The probability of adequate 3-month engraftment increased with the dose of CD34+ cells transplanted, but 10% of patients receiving > 5 x 10(6)/kg still showed poor engraftment at 3 months. However, all patients receiving > 2.5 x 10(5)/kg CD34+Thy-1+ showed adequate engraftment at this time point. We also demonstrated that CD34+Thy-1+ progenitors were restricted to the bone marrow under normal conditions and, during stem cell mobilization, their kinetics generally paralleled total CD34+ numbers.

ADP-ribosyl Cyclase↗

PubMed2001

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/mm(2) 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.

Angiotensin II↗

PubMed2001

Risk factors and mortality associated with calciphylaxis in end-stage renal disease.

BACKGROUND: We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. METHODS: Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. RESULTS: Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR = 0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P < 0.001). CONCLUSIONS: Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.

Alkaline Phosphatase↗

PubMed2001

Vascular endothelial growth factor (VEGF121) protects rats from renal infarction in thrombotic microangiopathy.

BACKGROUND: Renal thrombotic microangiopathy, typified by the hemolytic uremic syndrome, is associated with endothelial cell injury in which the presence of cortical necrosis, extensive glomerular involvement, and arterial occlusive lesions correlates with a poor clinical outcome. We hypothesized that the endothelial survival factor vascular endothelial growth factor (VEGF) may provide protection. METHOD: Severe, necrotizing, thrombotic microangiopathy was induced in rats by the renal artery perfusion of antiglomerular endothelial antibody, followed by the administration of VEGF or vehicle, and renal injury was evaluated. RESULTS: Control rats developed severe glomerular and tubulointerstitial injury with extensive renal necrosis. The administration of VEGF significantly reduced the necrosis, preserved the glomerular endothelium and arterioles, and reduced the number of apoptotic cells in glomeruli (at 4 hours) and in the tubulointerstitium (at 4 days). The prosurvival effect of VEGF for endothelium may relate in part to the ability of VEGF to protect endothelial cells from factor-induced apoptosis, as demonstrated for tumor necrosis factor-alpha (TNF-alpha), which was shown to be up-regulated through the course of this model of renal microangiopathy. Endothelial nitric oxide synthase expression was preserved in VEGF-treated rats compared with its marked decrease in the surviving glomeruli and interstitium of the antibody-treated rats that did not receive VEGF. CONCLUSIONS: VEGF protects against renal necrosis in this model of thrombotic microangiopathy. This protection may be mediated by maintaining endothelial nitric oxide production and/or preventing endothelial cell death.

Animals↗

PubMed2001

Role of immunocompetent cells in nonimmune renal diseases.

Renal infiltration with macrophages and monocytes is a well-recognized feature of not only immune, but also nonimmune kidney disease. This review focuses on the investigations that have shown accumulation of immunocompetent cells in experimental models of acute and chronic ischemia, protein overload, hypercholesterolemia, renal ablation, obstructive uropathy, polycystic kidney disease, diabetes, aging, murine hypertension, and nephrotoxicity. We examine the mechanisms of infiltration of immunocompetent cells and their participation in the self-perpetuating cycle of activation of the angiotensin system, generation of reactive oxygen species, and further recruitment of monocytes and lymphocytes. We also discuss the possibility of antigen-dependent and antigen-independent mechanisms of immune cell activation in these animal models. Finally, we review the recent studies in which suppression of cellular immunity with mycophenolate mofetil has proven beneficial in attenuating or preventing the progression of renal functional and histologic damage in experimental conditions of nonimmune nature.

Animals↗

PubMed2001

Chronic potassium depletion induces renal injury, salt sensitivity, and hypertension in young rats.

BACKGROUND: Chronic hypokalemia has been associated with renal hypertrophy, interstitial disease, and hypertension in both adult animals and humans. However, the effects of potassium (K(+)) depletion on the rapidly growing infant have not been well studied. The purpose of this study was to determine the effects of severe chronic dietary K(+) depletion on blood pressure (BP) and renal structural changes in young rats. METHODS: Sprague-Dawley rats (50 +/- 5 g) were fed either a control or a potassium-deficient diet (<0.05% K(+)) for 14 to 21 days. At the end of this period, the blood pressure (BP) was measured in all rats, and six rats in each group were sacrificed to determine changes in renal histology and renin-angiotensin system (RAS) activity. The remaining rats in each group were then switched to a high-salt (6% NaCl)--normal-K(+) (0.5%) diet or were continued on their respective control or K(+)-deficient diet for an additional six days. Blood pressure measurements were done every three days until the end of the study. RESULTS: K(+)-depleted animals had significant growth retardation and increased RAS activity, manifested by high plasma renin activity, recruitment of renin-producing cells along the afferent arterioles, and down-regulation of angiotensin II receptors in renal glomeruli and ascending vasa rectae. K(+)-depleted kidneys also showed tubulointerstitial injury with tubular cell proliferation, osteopontin expression, macrophage infiltration, and early fibrosis. At week 2, K(+)-depleted rats had higher systolic BP than control rats. Switching to a high-salt (6% NaCl)--normal-K(+) diet resulted in further elevation of systolic BP in K(+)-depleted rats, which persisted even after the serum K(+) was normalized. CONCLUSION: Dietary potassium deficiency per se increases the BP in young rats and induces salt sensitivity that may involve at least two different pathogenic pathways: increased RAS activity and induction of tubulointerstitial injury.

Animals↗

PubMed2001

Osteopontin expression in human cyclosporine toxicity.

BACKGROUND: Osteopontin is a secreted phosphoprotein that has a number of diverse biological functions, including cell signaling, mediation of cell adhesion, migration, and chemoattraction of monocytes/macrophages. Up-regulation of osteopontin expression by proximal tubular epithelium has been demonstrated in both human and rodent models of renal injury in association with macrophage influx. METHODS: We studied the expression of osteopontin protein and mRNA in renal donor biopsies (N = 7) and renal transplant biopsies with cyclosporine A toxicity (N = 23) by immunohistochemistry and in situ hybridization. Serial tissue sections were immunostained with a monocyte/macrophage marker, CD68, to demonstrate the pattern of macrophage infiltration. RESULTS: Strong osteopontin expression was observed in the majority of pretransplant donor biopsies in the absence of any macrophage infiltration. In the biopsies with cyclosporine toxicity, osteopontin expression was widespread and demonstrated moderate immunohistochemical signal intensity that did not correlate with the number of interstitial macrophages present. CONCLUSIONS: Strong osteopontin protein and mRNA expression by tubular epithelium was observed in pretransplant donor biopsies and in biopsies with cyclosporine toxicity without an inflammatory cell infiltration. Therefore, osteopontin expression alone is insufficient to serve as the principal mediator of intrarenal monocyte/macrophage influx in the transplant setting.

Biopsy, Needle↗

PubMed2001

Intravenous immunoglobulin protects against experimental thrombotic microangiopathy.

BACKGROUND: Intravenous immunoglobulin (IVIG) has been utilized in several forms of vasculitis and has many potential mechanisms of action, including the inhibition of C3 activation. We have previously demonstrated that IVIG can reduce glomerular injury in a model of membranous nephropathy mediated by C5b-9 [1]. C5b-9 has also been shown to mediate the thrombotic microangiopathy (TMA) induced by antibody to glomerular endothelial cells leading to a hemolytic uremic syndrome-type lesion [2]. METHODS: To test the hypothesis that IVIG might be effective in treating antibody-induced TMA, male uninephrectomized rats underwent right renal artery perfusion with goat anti-rat glomerular endothelial cell (GEN) antibody (20 mg/kg). Sheep IgG (200 mg/kg) was administered either 30 minutes before the renal artery perfusion (group I, N = 6) or 30 minutes postperfusion (group II, N = 9). A third control group received phosphate-buffered saline (PBS; group III, N = 12). A survival biopsy was performed at 15 minutes, and the animals were sacrificed on day 2. RESULTS: There were no significant differences in proteinuria or hematocrit between the groups. Animals pretreated with IVIG had significantly improved survival and renal function, which was associated with a decrease in glomerular C3 deposition. The protective effect of IVIG was abolished if the administration was delayed 30 minutes after perfusion. CONCLUSIONS: IVIG is effective in reducing injury in experimental TMA only if given prophylactically. The effect is mediated by inhibition of local intraglomerular complement activation.

Animals↗

PubMed2001

Subclinical renal injury induced by transient cyclosporine exposure is associated with salt-sensitive hypertension.

Cyclosporine use is highly associated with the development of salt-sensitive hypertension. We hypothesized that subtle renal injury induced by cyclosporine could lead to salt sensitivity. Cyclosporine nephropathy was induced by treatment for 4 weeks with cyclosporine (15 mg/kg/day) on a low sodium (0.05%) diet, followed by stopping cyclosporine and placement on a high sodium (4%) diet for 4 additional weeks. Control groups included a group treated with cyclosporine (15 mg/kg/day) on a normal salt diet in which nephropathy does not develop, and a vehicle-treated group. A fourth group received half-dose of cyclosporine (8 mg/kg/day) on a low sodium diet, which results in mild nephropathy. Biopsies were obtained at the end of the cyclosporine administration (4 week) and at sacrifice (8 week), and blood pressure and renal function were measured. Rats treated with cyclosporine for 4 weeks on a low sodium diet developed classic features of tubulointerstitial disease and arteriolopathy; these changes were absent in the cyclosporine/normal salt group and in the vehicle group. At 4 weeks, all groups were switched to a high salt diet; only the rats with nephropathy developed hypertension. The degree of hypertension correlated closely with the degree of tubulointerstitial injury (r=0.85) and with the severity of the arteriolopathy (r=0.9) (p<0.0.1). Importantly, renal function (creatinine clearance) was normal in all groups at 8 weeks, documenting that the hypertension could not be attributed to cyclosporine-mediated alterations in glomerular filtration rate (GFR). One mechanism by which cyclosporine induces hypertension is the induction of subtle renal microvascular and tubulointerstitial disease. This mechanism is not dependent on GFR and may persist even after the cyclosporine is discontinued.

Animals↗

PubMed2001

Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease.

We investigated the relationship of changes in the microvasculature to age-related structural and functional changes in the kidney to determine whether there was evidence of impaired angiogenesis and whether the loss of microvasculature could be accounted for by changes in the local production of angiogenic or antiangiogenic factors. Glomerular and peritubular capillary number, density, and endothelial cell proliferation were determined in aging (24 months; n = 9) and young (3 months; n = 8) rat kidneys and correlated with renal functional and structural changes and alterations in renal expression of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1). Aging rats showed a focal decrease in both peritubular capillary (peritubular capillary staining, 5.4% +/- 1.8% versus 11.3% +/- 2.0% per 100 tubules; rarefaction index, 10.6% +/- 4.6% versus 0.6% +/- 0.1%, aging versus young rats; P < 0.05 and P: < 0.001, respectively) and glomerular capillary loops (27.3 +/- 6.9 versus 50.7 +/- 7.4/glomerulus, aging versus young rats; P < 0.001). The number of proliferating endothelial cells was decreased in aging rats compared with young rats (glomerular, 0.04 +/- 0.01 versus 0.15 +/- 0.03 positive cells/glomerular cross-section; peritubular, 0.7 +/- 0.2 versus 4.3 +/- 2.6 positive cells/mm(2); P < 0.05). In the aging kidney, VEGF expression was focally increased in the cortex compared with young rats, whereas a profound decrease was observed in the outer and inner medulla (total area of VEGF expression, 19.2% +/- 11.4% versus 39.3% +/- 7.6%; P < 0.05). Tubular VEGF expression correlated with peritubular capillary density (r(2) = 0.57; P < 0.01) and inversely correlated with tubular osteopontin (r(2) = -0.55; P < 0.05) and macrophage infiltration (r(2) = -0.64; P < 0.01). TSP-1 staining was increased in the glomeruli and tubulointerstitium of the aging rats. Glomerular TSP-1 score correlated inversely with glomerular capillary number (r(2) = -0.89; P < 0.001). Tubulointerstitial TSP-1 also correlated with percentage of positive staining of peritubular capillary (r(2) = -0.59; P < 0.001). Glomerular capillary number showed significant correlation with glomerulosclerosis score, as well as with 24-hour urinary protein excretion. Peritubular capillary density also inversely correlated with interstitial fibrosis score and urinary protein excretion. In conclusion, glomerular and peritubular capillary loss in the aging kidney correlate with alterations in VEGF and TSP-1 expression and also with the development of glomerulosclerosis and tubulointerstitial fibrosis. These findings suggest that impaired angiogenesis associated with progressive loss in renal microvasculature may have a pivotal role in age-related nephropathy.

Aging↗

PubMed2001

Effect of an ET(B)-selective and a mixed ET(A/B) endothelin receptor antagonist on venomotor tone in deoxycorticosterone-salt hypertension.

OBJECTIVES: Because the ET(B) receptor is important in venoconstriction, we examined the effects of a selective ET(B) receptor antagonist (A-1 92621) and a mixed ET(A/B) receptor antagonist (A-182086) on endogenous endothelin-1 (ET-1) contributions to elevated venomotor tone in deoxycorticosterone acetate-salt (DOCA-salt) hypertension. METHODS: Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, DOCA-salt-treated rats and uninephrectomized sham rats following intravenous (i.v.) injections of the ET(B) antagonist (12 mg/kg i.v.) or the ET(A/B) antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.). RESULTS: DOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ET(A/B) receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ET(B) antagonist produced no changes in MCFP while MABP increased in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, with either antagonist produced greater declines in MCFP following hexamethonium than after hexamethonium alone. CONCLUSIONS: The present study confirms previous findings of elevated MCFP in DOCA-salt hypertensive rats compared to normotensive rats, but is the first to show that venomotor tone is affected by the actions of endogenous ET-1 acting at ET(B) receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ET(A) receptors. We also showed that mixed ET(A/B) receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.

Animals↗

PubMed2001

Factors affecting endothelin-induced venous tone in conscious rats.

There may be a relation between altered venous function, endothelin (ET)-1, and an impairment in the activity of endothelial-derived nitric oxide (NO) and prostanoids in salt-dependent hypertension. The present study examined the effects of salt intake on ET-induced changes in venomotor tone and the effects of blockade of NO synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) and of cyclooxygenase with indomethacin on venomotor tone caused by the ET(B) selective agonist sarafotoxin 6c (S6c) in awake rats. Rats were anesthetized for permanent placement of catheters for measurements of arterial and venous pressures. A silicone balloon catheter was also fixed in the right atrium to produce brief circulatory arrest. Venomotor tone was estimated from measurements of mean circulatory filling pressure (MCFP) in conscious rats. There were no differences in mean arterial pressure, heart rate, or MCFP responses to short-term administration of ET-1 or S6c at different levels of salt intake. L-NAME or indomethacin did not change MCFP or the response of MCFP to short-term injection of S6c. In conclusion, neither basal MCFP nor integrated venomotor responses to short-term injection of ET-1 or S6c were altered by short-term changes in salt intake, blockade of NO synthase or cyclooxygenase. These data do not support the hypothesis that increased salt intake alters reactivity of veins to ET-1, NO, or prostanoids.

Animals↗

PubMed2001

Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor.

Recent studies have demonstrated a role for microvascular and tubulointerstitial injury in some models of salt-sensitive hypertension. We utilized a model of post-cyclosporin A (CsA) nephropathy and hypertension to test the hypothesis that treatment with an angiogenic factor aimed at ameliorating the microvascular and renal injury would prevent the development of hypertension. CsA was administered with a low-salt diet for 45 days, resulting in a renal lesion characterized by afferent arteriolopathy, focal peritubular capillary loss, and tubulointerstitial fibrosis. Rats were then placed on a high-salt diet and randomized to receive either vascular endothelial growth factor (VEGF(121)) or vehicle for 14 days. Placement of rats with established CsA nephropathy on a high-salt diet results in the rapid development of salt-sensitive hypertension. VEGF(121) treatment resulted in lower blood pressure, and this persisted on discontinuing the VEGF. VEGF(121) treatment was also associated with a decrease in osteopontin expression, macrophage infiltration, and collagen III deposition and markedly stimulated resolution of the arteriolopathy (20.9 +/- 7.8 vs. 36.9 +/- 6.1%, VEGF vs. vehicle, P < 0.05). In conclusion, CsA-associated renal microvascular and tubulointerstitial injury results in the development of salt-sensitive hypertension. Treatment of animals with established CsA nephropathy with VEGF reduces the hypertensive response and accelerates histological recovery. The vascular protective effect of VEGF may be due to the improvement of arteriolopathy. Angiogenic growth factors may represent a novel strategy for treating CsA-associated hypertension and renal disease.

Animals↗

PubMed2001

Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition.

Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.

Animals↗

PubMed2001

Hypokalemia induces renal injury and alterations in vasoactive mediators that favor salt sensitivity.

We investigated the hypothesis that hypokalemia might induce renal injury via a mechanism that involves subtle renal injury and alterations in local vasoactive mediators that would favor sodium retention. To test this hypothesis, we conducted studies in rats with diet-induced K+ deficiency. We also determined whether rats with hypokalemic nephropathy show salt sensitivity. Twelve weeks of hypokalemia resulted in a decrease in creatinine clearance, tubulointerstitial injury with macrophage infiltration, interstitial collagen type III deposition, and an increase in osteopontin expression (a tubular marker of injury). The renal injury was greatest in the outer medulla with radiation into the cortex, suggestive of an ischemic etiology. Consistent with this hypothesis, we found an increased uptake of a hypoxia marker, pimonidazole, in the cortex. The intrarenal injury was associated with increased cortical angiontensin-converting enzyme (ACE) expression and continued cortical angiotensin II generation despite systemic suppression of the renin-angiotensin system, an increase in renal endothelin-1, a decrease in renal kallikrein, and a decrease in urinary nitrite/nitrates and prostaglandin E(2) excretion. At 12 wk, hypokalemic rats were placed on a normal-K+ diet with either high (4%)- or low (0.01%)-NaCl content. Despite correction of hypokalemia and normalization of renal function, previously hypokalemic rats showed an elevated blood pressure in response to a high-salt diet compared with normokalemic controls. Hypokalemia is associated with alterations in vasoactive mediators that favor intrarenal vasoconstriction and an ischemic pattern of renal injury. These alterations may predispose the animals to salt-sensitive hypertension that manifests despite normalization of the serum K+.

Angiotensin II↗

PubMed2001

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

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

Angiotensin II↗

PubMed2001

Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.

An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (r=0.75, n=69), with a 10-mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase.

Animals↗