PubMed Health⌕ Search

Biomedical subjects

Richard J Johnson

Publications and source records attributed to Richard J Johnson.

At least 19 recordsLinked to original sources
PubMed2007

Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy.

The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

Animals↗
PubMed2007

The role of uric acid in pediatric hypertension.

Over the past few years, increasing evidence has supported the possible role of uric acid as a mediator of high blood pressure. Both animal model data and tissue culture experiments suggest that uric acid might cause increased blood pressure through a 2-phase process. The first phase is dominated by a uric acid-mediated vasoconstriction followed by induction of renal afferent arteriolosclerosis and altered pressure natriuresis, leading to sodium-dependent hypertension. We have assessed children with newly diagnosed essential hypertension through cross-sectional studies and clinical trials. Elevated uric acid is closely associated with new-onset essential hypertension in children, and preliminary data suggest that lowering of uric acid can lower blood pressure in some patients. Future studies will be needed to determine whether the mechanisms shown in animal models can be extrapolated to children.

Adolescent↗
PubMed2007

Effect of elevated serum uric acid on cisplatin-induced acute renal failure.

Marked hyperuricemia is known to cause acute renal failure via intrarenal crystal deposition. However, recent studies suggest mild hyperuricemia may have vasoactive and proinflammatory effects independent of crystal formation. We therefore tested the hypothesis that mild hyperuricemia might exacerbate renal injury and dysfunction in a model of cisplatin-induced acute renal failure in the rat. Cisplatin was administered to normouricemic and hyperuricemic rats (the latter generated by administering the urate oxidase inhibitor, oxonic acid). Recombinant urate oxidase (rasburicase) was administered in a third group to assess the effect of lowering uric acid on outcomes. Other control groups include normal rats and hyperuricemic rats without cisplatin-induced injury. Cisplatin induced injury of the pars recta (S3) segment of the proximal tubule in association with a mild monocyte infiltration. Hyperuricemic rats showed significantly greater tubular injury and proliferation with significantly greater macrophage infiltration and increased expression of monocyte chemoattractant protein-1. However, renal function was not different between normouricemic and hyperuricemic rats with cisplatin injury. Treatment with rasburicase reversed the inflammatory changes and lessened tubular injury with an improvement in renal function (relative to the hyperuricemic group). No intrarenal crystals were observed in any groups. These data provide the first experimental evidence that uric acid, at concentrations that do not cause intrarenal crystal formation, may exacerbate renal injury in a model of acute renal failure. The mechanism may relate to a proinflammatory pathway involving chemokine expression with leukocyte infiltration.

Acute Kidney Injury↗
PubMed2006

Effects of acute and chronic L-arginine treatment in experimental hyperuricemia.

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.

Animals↗
PubMed2006

Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events?

We tested the hypothesis that endothelial dysfunction could cause placentation-related defects, persist after the complicated pregnancy, and probably cause cardiovascular disease later in life. Brachial arterial reactivity and factors related to endothelial dysfunction, such as circulating cholesterol, uric acid, nitrites, l-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1, in women with previous healthy pregnancies (n=22), patients with severe preeclampsia (n=25), or patients with recurrent pregnancy loss (n=29), at day 10 of the luteal phase of an ovulatory cycle an average of 11 to 27 months after pregnancy were evaluated. Both groups with placentation defects had a significant decrease in endothelium-dependent dilatation, a higher rate of endothelial dysfunction, lower serum nitrites, and higher cholesterol as compared with control subjects; subjects with previous preeclampsia additionally had higher normal blood pressures and a greater parental prevalence of cardiovascular disease. Patients with recurrent pregnancy loss also demonstrated a significantly lower endothelium-independent vasodilatation. A trend to an inverse correlation was found between serum cholesterol serum and endothelial-mediated vasodilatation in the whole study population. Uric acid, l-arginine, asymmetrical dimethylarginine, vascular endothelial growth factor, and soluble vascular endothelial growth factor receptor-1 were similar in all of the groups. We postulate that endothelial dysfunction may represent a link between preeclampsia and increased cardiovascular disease latter in life and propose that women with unexplained recurrent miscarriages are also at increased cardiovascular risk. The identification and correction of endothelial dysfunction detected during the reproductive stage on obstetric outcome and on cardiovascular diseases needs to be elucidated.

Abortion, Habitual↗
PubMed2006

Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats.

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.

Animals↗
PubMed2006

Angiotensin II, interstitial inflammation, and the pathogenesis of salt-sensitive hypertension.

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.

Angiotensin II↗
PubMed2006

Does Tamm-Horsfall protein-uric acid binding play a significant role in urate homeostasis?

BACKGROUND: Mutations in Tamm-Horsfall protein (THP), also known as uromodulin, lead to a group of diseases known as the uromodulin storage disorders. Clinically, these diseases present with tubulo-interstitial damage, progressive renal dysfunction, hyperuricaemia, and gout. However, it remains unclear how a mutation in THP, a protein produced in the thick ascending limb, can cause hyperuricaemia when most of the uric acid transport is believed to occur in the proximal tubule. However, one study in humans suggests that uric acid could also be secreted in the distal tubule. Thus, an attractive hypothesis could be that THP would bind to uric acid in the distal tubule, and decrease its subsequent reabsorption in the distal nephron. METHODS: We screened for uric acid binding to THP using four independent binding assays. RESULTS: There was no evidence that uric acid could bind to THP. CONCLUSION: THP-uric acid binding does not seem to play a significant role in the regulation of urate homeostasis.

Albumins↗
PubMed2006

Everolimus inhibits glomerular endothelial cell proliferation and VEGF, but not long-term recovery in experimental thrombotic microangiopathy.

BACKGROUND: Everolimus is a potent immunosuppressant used in renal transplant therapy, but its effects on renal endothelial cell regeneration after injury are unknown. The effects of an everolimus therapy were investigated in a model of renal thrombotic microangiopathy (TMA) with specific endothelial cell (EC) injury in the rat in vivo as well as in glomerular ECs in vitro. METHODS: During the early regenerative phase (day 3) of the renal microvascular injury model in vivo, everolimus inhibited glomerular EC proliferation by up to 60% compared with vehicle-treated rats, whereas apoptosis was not different in these groups. This decreased EC proliferation was associated with an enhanced deposition of fibrin in everolimus treated animals on day 3. In cultured glomerular endothelial cells, everolimus effectively and dose dependently inhibited cellular proliferation. This anti-proliferative effect was associated with a reduced phosphorylation of the p70S6 kinase and reduction of the pro-angiogenic factor VEGF in glomeruli in vivo and in cultured podocytes in vitro. RESULTS: Despite the prolonged EC repair and in contrast to the anti-Thy1 nephritis model, everolimus therapy did not disturb the long-term repair reaction in this thrombotic microangiopathy model. CONCLUSION: Everolimus is anti-proliferative for glomerular EC in vitro and in vivo and does not seem to have detrimental long-term effects in experimental renal TMA, when only the glomerular endothelium, but not the mesangium is severely injured.

Animals↗
PubMed2006

Vascular endothelial growth factor administration does not improve microvascular disease in the salt-dependent phase of post-angiotensin II hypertension.

Renal microvascular injury and tubulointerstitial inflammation may provide a potential mechanism for the development of salt-sensitive hypertension. Therefore, we hypothesized that vascular endothelial growth factor (VEGF) administration would prevent the development of salt-sensitive hypertension induced by ANG II. Infusion of ANG II in rats for 2 wk led to an elevation in blood pressure and an increase in blood urea nitrogen. Prominent tubular injury, focal areas of peritubular capillary loss accompanied by a decrease in urinary nitrites, thickening of the afferent arteriole, and an elevation in systemic and renal VEGF protein levels also occurred. In separate studies, animals were infused with ANG II and then placed on a low-salt diet for 1 wk. At this point, the animals were paired on the basis of weight and blood pressure and treated with either VEGF(121) or vehicle subcutaneously for 8 wk while being fed a high-salt diet. During the treatment period, a spontaneous improvement in many parameters, including both renal function and healing of the peritubular capillaries, occurred to the same degree in both vehicle- and VEGF(121)-treated rats. VEGF(121) significantly reduced blood pressure and accelerated the recovery of tubular injury. In contrast, vehicle-treated rats demonstrated a persistent increase in afferent arteriolar media-to-lumen ratio, which was further enhanced in rats treated with VEGF(121). Therefore, VEGF therapy has only limited benefits on the healing of renal lesions in the salt-dependent phase of post-ANG II-mediated hypertension.

Angiotensin II↗
PubMed2006

Human vascular smooth muscle cells express a urate transporter.

An elevated serum uric acid is associated with the development of hypertension and renal disease. Renal regulation of urate excretion is largely controlled by URAT1 (SLC22A12), a member of the organic anion transporter superfamily. This study reports the specific expression of URAT1 on human aortic vascular smooth muscle cells, as assessed by reverse transcription-PCR and Western blot analysis. Expression of URAT1 was localized to the cell membrane. Evidence that the URAT1 transporter was functional was provided by the finding that uptake of 14C-urate was significantly inhibited in the presence of probenecid, an organic anion transporter inhibitor. It is proposed that URAT1 may provide a mechanism by which uric acid enters the human vascular smooth muscle cell, a finding that may be relevant to the role of uric acid in cardiovascular disease.

Aorta↗
PubMed2006

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome.

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.

Capillary Permeability↗
PubMed2006

Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy.

The role of VEGF in vascular disease is complicated. Vascular endothelial growth factor (VEGF) expression can be deleterious in diabetic vasculopathy, especially in kidney and retina. In contrast, VEGF seems to be renoprotective in nondiabetic renal disease. VEGF exerts it biologic effects in association with nitric oxide (NO), yet it is known that NO bioavailability is reduced in diabetes. Thus, it was hypothesized that this diverse biologic effect of VEGF on diabetic vasculopathy is due to uncoupling of VEGF with NO. VEGF stimulated NO production in a dose-dependent manner in bovine aortic endothelial cells (BAEC), and this was inhibited by either high glucose or Nomega-nitro-l-arginine methyl ester (L-NAME) treatment. Endothelial NO synthase phosphorylation by VEGF was also inhibited by high glucose. It is interesting that both high glucose and L-NAME enhanced the proliferative response of endothelial cells, which was prevented by an NO donor. Furthermore, high glucose as well as L-NAME stimulated VEGF and kinase-insert domain receptor (KDR) (VEGF receptor 2) mRNA expression in BAEC. These data suggest that the uncoupling of VEGF with NO enhances endothelial cell proliferation via the KDR pathway. Compatible with these findings, a KDR antagonist blocked this response. In addition, a VEGF mutant, which binds only KDR, induced extracellular signal-regulated kinase (ERK) activation, and inhibition of ERK completely blocked endothelial cell proliferation under this condition, suggesting a role of the KDR-ERK1/2 pathway on endothelial cell proliferation. In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway. These results may provide new insights into the understanding of the mechanism of diabetic vascular disease.

Animals↗
PubMed2006

Effectiveness of nesiritide on dialysis or all-cause mortality in patients undergoing cardiothoracic surgery.

BACKGROUND: Natriuretic peptides have been shown to have favorable renal effects. However, recent evidence suggests potential renal side effects in patients with congestive heart failure. HYPOTHESIS: This study examined the effect of nesiritide (human B-type natriuretic peptide) on hemodialysis or death in patients undergoing cardiothoracic surgery. METHODS: This retrospective cohort study included patients (n = 940) undergoing nontransplant adult cardiothoracic surgery between July 2001 and February 2004. Patients receiving nesiritide within 3 days after and not before surgery (n = 151) were compared with those not given nesiritide (n = 789) for incidence of hemodialysis or in-hospital death by Day 21 (HD/death). Patients with preexisting dialysis and intraoperative deaths were excluded. Forward inclusion multiple logistic regression was used based on published risk factors for HD/death. RESULTS: Of 940 patients (318 coronary artery bypass graft, 348 valve, and 274 thoracic aorta), 36 required dialysis and 60 patients died (HD/death; n = 77). Adjusted for significant confounders (gender, age, procedure, intra-aortic balloon, baseline serum creatinine mg/dl [SCr], 1 day % SCr increase), nesiritide showed a statistically nonsignificant HD/death reduction (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.29-1.17; p = 0.129) in the group as a whole. When stratified by baseline SCr, a significant benefit was noted in patients with SCr > 1.0 (OR, 0.35; 95% CI 0.14-0.87; p = 0.024), while no significant effect was found in patients with SCr < 1.0 (OR, 1.55; 95% CI 0.48-5.07, p = 0.465). CONCLUSIONS: Nesiritide appears promising in reducing the risk of dialysis or death in patients with SCr > 1.0 undergoing cardiothoracic surgery; however, no effect was noted with SCr < 1.0. This study provides strong rationale for a randomized trial.

Acute Kidney Injury↗
PubMed2006

Uric acid and hypertension.

Epidemiologic studies published during the past 3 years support the possible role of uric acid in the onset of essential hypertension. Data from several large, longitudinal cardiovascular disease studies indicate that elevated serum uric acid is a predictor of incident hypertension and blood pressure progression. In a pediatric study, more than 90% of children with essential hypertension have serum uric acid levels above 5.5 mg/dL. During the same period, laboratory studies have provided compelling mechanistic evidence to explain the clinical observations. Uric acid causes hypertension in a rat model through the activation of the renin-angiotensin system, downregulation of nitric oxide, and induction of endothelial dysfunction and vascular smooth muscle proliferation. Ongoing clinical trials will elucidate the role of uric acid in human hypertension and will determine whether control of uric acid may be a new way to prevent or treat essential hypertension.

Animals↗
PubMed2006

J-shaped mortality relationship for uric acid in CKD.

BACKGROUND: Hyperuricemia is a common feature in patients with chronic kidney disease (CKD). Hyperuricemia has been associated with increased cardiovascular mortality in the general population, but less is known about this association in patients with CKD. METHODS: To explore possible associations of serum uric acid with all-cause mortality and comorbidity in patients with CKD, we studied 294 incident patients with CKD stage 5 (185 men; age, 53 +/- 12 years) starting renal replacement therapy with a median glomerular filtration rate of 6.4 mL/min/1.73 m(2) (0.11 mL/s/1.73 m(2); range, 0.8 to 14.3 mL/min/1.73 m(2) [0.01 to 0.24 mL/s/1.73 m(2)]). Survival was determined from the day of examination and during a mean follow-up period of 27 months (range, 3 to 72 months); 94 patients died. Patients were divided into 3 groups based on serum uric acid levels (low quintile, 3 middle quintiles, and high quintile). RESULTS: In a nonadjusted analysis, patients in the high quintile, followed by patients in the low quintile, had greater all-cause mortality compared with patients in the 3 middle quintiles (log-rank test chi-square, 6.8; P = 0.03). After adjusting for age, sex, glomerular filtration rate, cholesterol level, phosphate level, C-reactive protein level, cardiovascular disease, diabetes mellitus, diuretics, and allopurinol treatment, the association showed a "J-shaped" association with hazard ratios of 1.96 (confidence interval, 1.10 to 3.48; P = 0.02) for the high quintile and 1.42 (confidence interval, 0.76 to 2.66; P = not significant) for the low quintile. Moreover, uric acid levels correlated positively with levels of triglycerides, phosphate, C-reactive protein, and intracellular adhesion molecule 1 and negatively with levels of calcium, high-density lipoprotein cholesterol, and apolipoprotein A. CONCLUSION: Serum uric acid levels showed a J-shaped association with all-cause mortality, with the lowest risk in the 3 middle quintiles. Moreover, uric acid level was associated with calcium/phosphate metabolism, dyslipidemia, and inflammation.

Adult↗