Biomedical subjects

Marie-Luise Gross

Publications and source records attributed to Marie-Luise Gross.

At least 19 recordsLinked to original sources

PubMed2006

Poly(ADP-ribose) polymerase inhibition combined with irradiation: a dual treatment concept to prevent neointimal hyperplasia after endarterectomy.

PURPOSE: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. METHODS AND MATERIALS: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. RESULTS: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. CONCLUSIONS: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

Animals↗

PubMed2006

Adult hypertension in intrauterine growth-restricted offspring of hyperinsulinemic rats: evidence of subtle renal damage.

In humans, intrauterine growth-restricted newborns are prone to develop hypertension as adults. We studied a rat model of pregnancy-induced hypertension associated with intrauterine growth restriction (IUGR) produced by chronic administration of insulin. Fetuses of hyperinsulinemic dams (HDs) were smaller than those of normal dams (5.1+/-0.4 g versus 5.6+/-0.1 g, respectively; P<0.05). At 16 weeks of age, tail-cuff systolic blood pressure was measured, the rats were placed in metabolic cages and euthanized, and the kidneys were examined. Male but not female offspring of HDs (n=9) had higher blood pressure than normal-pregnancy offspring (n=12; 148+/-11 mm Hg versus 118+/-14 mm Hg; P<0.004). In contrast to other models, there was no difference in ours in the number and volume of glomeruli. However, there were significantly greater glomerular, tubulointerstitial, and vascular damage indices in the kidneys of male HD offspring versus controls (2.01+/-0.34 versus 1.08+/-0.16, 1.80+/-0.34 versus 0.76+/-0.12, and 2.13+/-0.81 versus 0.78+/-0.16, respectively; P<0.0001), with similar tubulointerstitial findings in females. Increased expression of collagen type IV, a kidney damage marker indicating fibrosis, was found in the tubulointerstitium. This may be associated with downregulation of bone morphogenetic protein 6, a presumptive antifibrogenic agent, at the end of gestation. In conclusion, male offspring of HDs displayed IUGR and adult hypertension accompanied by several indices of renal fibrosing damage, mainly in the renal tubulointerstitium. Our findings suggest that there is >1 pathway of fetal programming leading from IUGR to development of hypertension in later life.

Animals↗

PubMed2006

Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation.

PURPOSE: The generation of reactive oxygen species during gamma-irradiation may induce DNA damage, leading to activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) culminating in endothelial dysfunction. In the present study, we assessed the effect of PARP inhibition on changes in vascular function after acute and short-term irradiation. METHODS AND MATERIALS: In the acute experiments, aortic rings were exposed to 20 Gy of gamma-irradiation. The aortae were harvested after 1 or 7 days. Two additional groups received the ultrapotent PARP inhibitor, INO-1001, for 1 or 7 days after irradiation. The aortic rings were precontracted by phenylephrine and relaxation to acetylcholine and sodium nitroprusside were studied. RESULTS: The vasoconstrictor response to phenylephrine was significantly lower both acutely and 1 and 7 days after irradiation. Vasorelaxation to acetylcholine and sodium nitroprusside was not impaired acutely after irradiation. One and seven days after irradiation, vasorelaxation to acetylcholine and sodium nitroprusside was significantly enhanced. Treatment with INO-1001 reversed vascular dysfunction after irradiation. CONCLUSION: Vascular dysfunction was observed 1 and 7 days after irradiation, as evidenced by reduced vasoconstriction, coupled with endothelium-dependent and -independent hyperrelaxation. PARP inhibition restored vascular function and may, therefore, be suitable to reverse vascular dysfunction after irradiation.

Acetylcholine↗

PubMed2006

Nonhypotensive dose of beta-adrenergic blocker ameliorates capillary deficits in the hearts of rats with moderate renal failure.

Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with alpha- and beta-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague-Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786+/-372 vs 3,397+/-602 mm/mm3); the decrease was abrogated by metoprolol (3,305+/-624 mm/mm3), but not by phenoxybenzamin (2,628+/-480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5+/-1.5 microm) and tended to be lower after metoprolol treatment (19.0+/-1.9 microm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158+/-1,343 vs 686+/-771 microm2 in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.

Adrenergic beta-Antagonists↗

PubMed2006

CD40-CD154 expression in calcified and non-calcified coronary lesions of patients with chronic renal failure.

The high incidence of cardiovascular complications in patients with chronic renal failure (CRF) is partly explained by more aggressive atherosclerosis, i.e. increased incidence and severity of lesions with higher tendency to calcification. The pathogenesis of this accelerated atherosclerosis, however, is not completely understood. Among other risk factors, chronic micro-inflammation may be involved. Activation of cells and adhesion molecules in atherosclerosis is governed by CD40-CD154 (CD40 ligand) interaction. Therefore, we investigated the expression and distribution of CD40-CD154 in different coronary atherosclerotic lesions of CRF patients and non-renal control patients. Coronary plaques of 57 patients with and without CRF were categorized according to the Stary classification and analysed for in situ protein expression of CD40, CD154 and CRP using immunohistochemistry and a semiquantitative scoring system. The nature, number and distribution of infiltrating cells was analysed and correlated to the types of coronary lesions and in particular to the presence of calcification. CD40 was over expressed in media myocytes of coronary plaques of both uremic and control patients. Inside the plaques, CD40 was expressed on endothelial cells, T lymphocytes, macrophages, fibroblasts, and smooth muscle cells. CD154 expression was seen on T cells in areas densely infiltrated by CD40 positive macrophages. In uremic and control patients higher in situ expression of CD40, CD154 and CRP was seen in calcified compared to non-calcified lesions. Inside the plaques, there were significant differences in the expression pattern of CD40 and CD154 between uremic and control patients. In addition, in uremic patients coronary plaques showed higher CRP protein expression compared to control patients. The data indicate a higher inflammatory status of coronary lesions as well as involvement of the CD40-CD154 signaling cascade in CRF patients, especially in cases of calcified atherosclerotic lesions.

Aged↗

PubMed2006

Comprehensive immunohistological analysis of the endothelin system in human kidney grafts.

BACKGROUND: In experimental models of renal transplantation, upregulation of the endothelin (ET) system and amelioration of renal injury by ET-receptor blockers have been documented. In contrast, little information is available on the expression of the ET system in human kidney allografts. It was the purpose of the present study to analyse by immunohistology the expression of ET-1 as well as of the two ET receptors (ET-RA and ET-RB) in the different cells and compartments of kidney grafts and control kidneys. METHODS: Fifty-five graft biopsies were taken from 55 kidney allograft recipients (mean age: 32+/-2.8 years) who were all on a calcineurin inhibitor. The indication for biopsies was delayed graft function or suspected rejection. The underlying diagnoses were acute allograft rejection (n = 14), chronic allograft nephropathy (n = 14), cyclosporin A (CSA) toxicity (n = 10), post-operative acute tubular necrosis (ATN) (n = 11) and recurrent primary disease (n = 6). As control, tissues of non-grafted kidneys with ATN (mean age: 35+/-24 years), of primary glomerulonephritis (mean age: 69+/-10 years) and of non-tumour-bearing parts of eight tumour nephrectomy specimens (mean age: 67+/-5 years) were assessed. The biopsies were scored using the 1997 Banff criteria. Expression of ET-1, ET-RA and ET-RB as well as of vascular endothelial growth factor was evaluated by immunohistochemistry and a semi-quantitative scoring system. Interstitial infiltrating cells were characterized using antibodies against T cells, B cells and macrophages (CD3, CD20 and CD68). RESULTS: Control cases showed only faint expression of ET-1 in glomeruli (in podocytes and endothelial cells), whereas marked expression was seen in distal, but less in proximal tubular cells. The interstitium was completely negative. ET-1 expression was seen in vascular endothelial cells (VEC) and vascular smooth muscle cells (VSMC). Only faint expression of ET-RA and ET-RB was found in glomeruli and tubuli (distal more than proximal). Marked ET-RA and ET-RB expression was seen in VEC and VSMC. In all transplanted kidneys, irrespective of the underlying diagnosis, expression of ET-1, ET-RA and ET-RB was markedly higher compared with control kidneys. ET-1 was strikingly upregulated in glomeruli and tubuli, but surprisingly not in the vasculature of grafts with CSA toxicity. Expression of ET-RB was markedly increased in CSA toxicity in glomeruli, tubuli and vessels. In grafts with ATN and acute rejection, pronounced expression of ET-RA was noted. There was a strong correlation between proteinuria and expression of ET-1 in glomeruli and proximal tubuli and of ET-RB in proximal tubuli. CONCLUSIONS: The above data in human kidney allograft biopsies are consistent with an important role of the ET system in different types of renal allograft damage. This finding extends and clarifies the somewhat contradictory results in animal models.

Acute Disease↗

PubMed2006

Adjunct brachytherapy: a new concept to prevent intimal hyperplasia after surgical endarterectomy?

OBJECTIVE: Endarterectomy represents a therapeutical option for patients with advanced coronary artery disease. The mid-term results are compromised by restenosis due to neointima formation. The aim of this study was to evaluate a new treatment concept - endarterectomy with consecutive gamma-irradiation - in a rat model. METHODS: Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n=10) or were irradiated with 15 Gray (Gy) (n=13) or 20 Gy (n=10) postoperatively and compared with sham-operated rats (n=10). After 3 weeks, carotid arteries were perfusion-fixed and vessel compartment areas were measured. Transmission electron microscopy and immunohistochemical staining were used to confirm neointima formation. RESULTS: Three weeks after endarterectomy, neointimal hyperplasia was found in the control group (0.07+/-0.04 mm(2)). After irradiation, a dose-dependent reduction of neointima was observed (0.003 mm(2) at 15 Gy and 0.0007 mm(2) at 20 Gy, P<0.0001). However, immunohistochemical staining revealed that thin re-endothelialization after irradiation was not inhibited. CONCLUSIONS: Gamma-irradiation significantly suppressed neointimal hyperplasia in a rat model of surgical endarterectomy. Despite inhibition of intimal hyperplasia, re-endothelialization after adjuvant brachytherapy was present. Adjuvant brachytherapy may be therefore a new concept to prevent restenosis after endarterectomy in patients.

Animals↗

PubMed2006

Analysis of pigmented villonodular synovitis with genome-wide complementary DNA microarray and tissue array technology reveals insight into potential novel therapeutic approaches.

OBJECTIVE: To characterize the gene expression profile and determine potential diagnostic markers and therapeutic targets in pigmented villonodular synovitis (PVNS). METHODS: Gene expression patterns in 11 patients with PVNS, 18 patients with rheumatoid arthritis (RA), and 19 patients with osteoarthritis (OA) were investigated using genome-wide complementary DNA microarrays. Validation of differentially expressed genes was performed by real-time quantitative polymerase chain reaction and immunohistochemical analysis on tissue arrays (80 patients with PVNS, 51 patients with RA, and 20 patients with OA). RESULTS: The gene expression profile in PVNS was clearly distinct from those in RA and OA. One hundred forty-one up-regulated genes and 47 down-regulated genes were found in PVNS compared with RA, and 153 up-regulated genes and 89 down-regulated genes were found in PVNS compared with OA (fold change > or = 1.5; Q < or = 0.001). Genes differentially expressed in PVNS were involved in apoptosis regulation, matrix degradation, and inflammation (ALOX5AP, ATP6V1B2, CD53, CHI3L1, CTSL, CXCR4, HSPA8, HSPCA, LAPTM5, MMP9, MOAP1, and SPP1). CONCLUSION: The gene expression signature in PVNS is similar to that of activated macrophages and is consistent with the local destructive course of the disease. The gene and protein expression patterns suggest that the ongoing proliferation in PVNS is sustained by apoptosis resistance. This result suggests the possibility of a potential novel therapeutic intervention against PVNS.

Arthritis, Rheumatoid↗

PubMed2005

Cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 in ischemia-reperfusion injury.

OBJECTIVE: The aims of the study were to visualize the dynamics of ischemia-reperfusion injury by real-time myocardial contrast echocardiography and to investigate the cardioprotective effects of the novel endothelin-A receptor antagonist BSF 461314. BSF 461314 reduced infarct size by 47% and preserved microvascular integrity. Real-time myocardial contrast echocardiography allowed visualization of postischemic microvascular dysfunction and quantification of cardioprotective effects of selective endothelin antagonism. Blood flow index A x beta was reduced in anterior segments during ischemia compared with baseline (0.06 +/- 0.01 vs 0.98 +/- 0.2 dB/s) but was higher in the BSF 461314 group after 120 minutes of reperfusion (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015). Therefore, selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time myocardial contrast echocardiography accurately detected changes in microvascular reflow. BACKGROUND: Endothelin-1 is a potent vasoconstrictor and elevated in myocardial ischemia. The aims of the study were to examine cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 and to visualize changes in the microvasculature by real-time myocardial contrast echocardiography (MCE). METHODS: A total of 16 open-chest pigs underwent 45 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. A total of 1 mg/kg BSF 461314 or vehicle was given intravenously before reperfusion. Serial MCE was performed to assess changes in myocardial blood flow A x beta and perfusion defect size. Myocardial blood flow was measured by fluorescent microspheres and infarct size was measured by triphenyltetrazolium chloride tissue staining. RESULTS: Dynamics of infarct size expansion and tissue perfusion were correctly assessed by MCE. A x beta Was reduced in anterior segments during left anterior descending coronary artery occlusion (0.06 +/- 0.01 dB/s) compared with baseline (0.98 +/- 0.2 dB/s), approached higher levels postrecanalization (1.2 +/- 0.1 dB/s), but gradually decreased during reperfusion (0.3 +/- 0.05 dB/s, P < .01). After 120 minutes of reperfusion A (2.1 +/- 0.5 vs 1.0 +/- 0.6 dB, P < .03), beta (0.36 +/- 0.09/s vs 0.21 +/- 0.09/s, P = .01), and A x beta (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015) in the risk area were higher in the BSF 461314-treated group compared with vehicle indicating preserved myocardial perfusion. Triphenyltetrazolium chloride staining confirmed a 47% reduction in infarct size by BSF 461314. CONCLUSIONS: Selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time MCE allows visual and quantitative evaluation of dynamics of myocardial ischemia-reperfusion injury and monitoring of cardioprotective effects during pharmacologic interventions.

Animals↗

PubMed2005

Effects of estrogens on cardiovascular structure in uninephrectomized SHRsp rats.

BACKGROUND: The risk of cardiovascular disease in uremic patients is greater in male than in female patients. Estrogens seem to play a cardioprotective role until menopause. Experimental data on the effect of estrogens on cardiovascular damage are controversial and potential underlying mechanisms especially in renal failure have not been fully clarified. METHODS: Three-month-old female uninephrectomized stroke-prone spontaneously hypertensive (SHRsp) rats were sham-operated or ovariectomized. Subsequently, they received either vehicle (sesame oil) or 17-beta-3 benzoate estradiol (E2) (25 microg/day) or estriol (E3) (0.02 mg/day), respectively. After 3 months the animals were sacrified and the organs were harvested using pressure-controlled perfusion fixation. Stereologic parameters such as capillary length density (L(V)), mean intercapillary distance (MID), and volume density of the interstitial tissue (Vv) were quantitated. Additionally, expression of transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), flt-1, endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), endothelin A receptor (ETA) receptor, and alpha estrogen receptor was assessed using immunohistochemistry. Intramyocardial capillaries and the aorta were investigated by morphometric methods. RESULTS: L(V) (mm/mm(3)) was significantly lower (2421 +/- 500) and MID (microm) significantly higher (22.2 +/- 2.33) in vehicle-treated uninephrectomized/ovariectomized compared to uninephrectomized/sham-ovariectomized controls (L(V) 3629 +/- 960, MID 12.7 +/- 2.7) as well as estradiol (L(V) 3340 +/- 739, MID 12.1 +/- 4.96) and estriol (L(V) 4655 +/- 618, MID 14.2 +/- 2.89) treated uninephrectomized/ovariectomized animals. The volume density of the cardiac interstitium was higher in vehicle-treated uninephrectomized/ovariectomized animals compared to uninephrectomized/sham-ovariectomized, estradiol and estriol treated uninephrectomized/ovariectomized rats. The protein level expression of TGF-beta was higher in vehicle treated uninephrectomized/ovariectomized compared to uninephrectomized/sham and all treatment groups. CONCLUSION: In ovariectomized SHRsp rats with moderate renal failure cardiac lesions were strikingly less after estradiol or estriol treatment. The results document a beneficial role of estrogens on cardiac abnormalities in a model of moderate renal dysfunction.

Animals↗

PubMed2005

Diabetic nephropathy: recent insights into the pathophysiology and the progression of diabetic nephropathy.

Diabetes has become the single most frequent comorbid condition in patients admitted for renal replacement therapy. This is the result of a greater prevalence of type 2 diabetes and better survival of diabetic patients. Progress has been made in pinpointing the predisposition to diabetes on metabolic abnormalities of muscle mitochondrial metabolism, but the long sought genes predisposing to diabetes and to diabetic nephropathy have not yet been identified. Of great concern are experimental studies documenting that maternal hyperglycemia causes nephron underdosing in the offspring. Relevant to pathogenesis and treatment of diabetic nephropathy are, among others, recent insights that hyperglycemia sensitizes target organs to blood pressure-induced damage, and that local renin-angiotensin systems play an important role in genesis and progression of diabetic nephropathy.

Diabetes Mellitus, Type 2↗

PubMed2005

Calcification and cardiovascular problems in renal failure.

Extraosseus calcification has plagued management of renal failure since the beginning of hemodialysis, but the issue has largely been neglected because the impact on survival was thought to be limited. The recent recognition that hyperphosphatemia is a strong predictor of all-cause mortality, and particularly of cardiac mortality, has transformed the situation. Relatively stringent, though difficult to implement, guidelines have been proposed for the management of hyperphosphatemia. Important recent insights document that, for different reasons, both high and low turnover of bone disease increase the risk of vascular calcifications. Vascular calcification impacts cardiac death not only by complicating coronary atherosclerosis, but also by increasing the stiffness of central arteries, impacting on heart function (increased impedance, reduced coronary perfusion). While in the past extraosseous calcification, including vascular calcification, was thought to be a passive process resulting from transgression of a critical Ca x P product, recent studies show that the adverse effect of hyperphosphatemia is also mediated by active processes (e.g., induction of "osteogenic" genetic programs), and is modulated by calcification inhibitors.

Calcinosis↗

PubMed2005

Role of calcium-phosphorous disorders in the progression of renal failure.

Among factors related to disturbed calcium-phosphate metabolism in chronic kidney disease, the following must be mainly considered as potential culprits in the progression of renal dysfunction: hyperphosphatemia, hyperparathyroidism, lack of active vitamin D, and possibly excess of the phosphaturic hormone FGF 23. Early experimental work suggested a parathyroid hormone (PTH)-independent beneficial role of phosphate restriction on progression in rats (animals with physiologic hyperphosphatemia), so that the generalization of the data is uncertain. Recent observational studies also found a correlation between S-phosphate and progression, but it remains uncertain whether the relationship is causal. There is very little direct experimental or clinical evidence for a role of PTH in accelerating progression, although the PTH1 receptor is expressed in podocytes and PTH affects podocyte function (i.e., Kf). It is undoubtedly a candidate that requires more sophisticated investigation. Recently, it has been shown that progression is significantly attenuated by calcimimetics (and equally by parathyroidectomy), but it is currently impossible to exclude a confounding effect of lower blood pressure values. The most solid evidence for an impact on progression exists for active vitamin D. In the past, it was widely assumed that vitamin D was "nephrotoxic." In retrospect, nephrotoxicity was the result of hypercalcemia. Recent evidence is overwhelming that 1,25(OH)2D3 and its analogues attenuate progression in noninflammatory and inflammatory models of chronic kidney disease. The main target cells identified so far are podocytes and mesangial cells. It is currently unknown whether the novel phosphaturic hormones have an impact on progression.

Aniline Compounds↗

PubMed2005

Hyperphosphatemia in renal failure.

The recent recognition that hyperphosphatemia is a strong predictor of survival on dialysis has rekindled interest in the regulation and control of serum phosphate. In incipient renal failure hyperphosphatemia is prevented by increased fractional renal phosphate excretion mediated via an increase in parathyroid hormone and the novel phosphaturic hormone FGF-23 (and possibly others). At a glomerular filtration rate of approximately 30 ml/min this compensatory mechanism fails and hyperphosphatemia ensues. Pre-dialytic serum phosphate concentrations of >6 mg/dl increase cardiac mortality presumably to a large extent, but not exclusively, via promoting vascular calcification. It has recently been recognized that vascular calcification is not only a passive precipitation process following transgression of the critical Ca-x-P product, but is an active process accompanied by expression of osteoblastic bone markers in the vessel wall. Because of the recent recognition of the relation between vascular calcification and serum phosphate as well as serum calcium, there is a need for novel calcium-free phosphate binders. Currently sevelamer and lanthanum carbonate have been introduced and trivalent iron preparations are under development.

Animals↗

PubMed2005

Hemodialysis--from early days to tomorrow.

The Nestor of chronic dialysis, Belding Scribner, was well aware of most problems which plague hemodialysis to this day, but the major problem we are confronted with today has emerged much later, i.e. excessive cardiovascular mortality. Apart from modulating duration and frequency of dialysis, there is currently no logistic or technological solution immediately apparent to solve this problem. Elucidating and correcting the cardiovascular risk is the most important challenge to clinical nephrology today.

Cardiovascular Diseases↗

PubMed2005

Nephron number and renal risk in hypertension and diabetes.

It has been proposed that "nephron underdosing," i.e., a low number of nephrons at the time of birth, is linked to essential hypertension and a greater propensity to develop progressive loss of renal function after renal injury. This hypothesis was confirmed recently by examining the number of glomeruli in patients with essential hypertension. The mechanisms through which a low number of nephrons causes hypertension have not been clarified, but it is likely that functional changes in postglomerular segments of the nephron, e.g., handling of sodium, play an important role. Neonatal uninephrectomy increases BP, renders BP salt sensitive, and renders the kidney more susceptible to damage. Apart from genetic factors, fetal/maternal malnutrition during pregnancy seems to play an important role in the pathogenesis of nephron underdosing. Furthermore, intrauterine programming during organogenesis, e.g., by hyperglycemia, seems to be important: In animal experiments, offspring of either hyperglycemic or diabetic mothers have fewer nephrons.

Animals↗

PubMed2004

Evaluation of cardioprotective effects of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in myocardial ischemia-reperfusion injury by real-time myocardial contrast echocardiography.

OBJECTIVES: The purpose was to examine the cardioprotective effects of recombinant P-selectin glycoprotein ligand-immunoglobulin (rPSGL-Ig) in ischemia-reperfusion injury by real-time myocardial contrast echocardiography (MCE). BACKGROUND: P-selectin mediates leukocyte recruitment into areas of inflammation. METHODS: Sixteen pigs underwent 45 min of left anterior descending coronary artery occlusion followed by reperfusion and received rPSGL-Ig or vehicle. To assess changes in myocardial perfusion (A x beta), MCE was performed. RESULTS: After 120 min of reperfusion, A x beta in the risk area was higher (0.84 +/- 0.15 dB/s vs. 0.28 +/- 0.1 dB/s, p < 0.0001), and the infarct size was lower (30.3 +/- 12% vs. 57 +/- 14%, p = 0.002) in the rPSGL-Ig group compared with the vehicle group. CONCLUSIONS: Recombinant PSGL-Ig improved postischemic reflow accurately detected by real-time MCE.

Animals↗

PubMed2004

Progression of renal disease: new insights into risk factors and pathomechanisms.

PURPOSE OF REVIEW: Progression of renal failure, irrespective of the primary cause, is characterized by modification of renal structure, which culminates in terminal renal insufficiency. Interfering with progression continues to be a major challenge and is at the forefront of renal research. This review focuses on recent progress in the understanding of the mechanisms of progression and efforts to interfere with this process. RECENT FINDINGS: In addition to the long-known risk factors (hypertension and inadequate activation of the renin-angiotensin system), several novel risk factors and pathomechanisms, such as obesity, hyperglycemia, smoking, and several hormones, have recently been identified and investigated. Furthermore, the specific and blood pressure-independent pathogenetic roles of the sympathetic nervous system and the endothelin system in progression have been further clarified. Finally, novel animal models and techniques for studying specific aspects of progression have been developed and introduced. SUMMARY: Recently, considerable progress has been made concerning novel risk factors, understanding the underlying pathomechanisms, and interfering with the course of progression of renal diseases. Such improved insights will undoubtedly lead to new strategies in the future.

Animals↗