Biomedical subjects

Radko Komers

Publications and source records attributed to Radko Komers.

12 recordsLinked to original sources

PubMed2006

Renal effects of HMG-CoA reductase inhibition in a rat model of chronic inhibition of nitric oxide synthesis.

BACKGROUND/AIMS: In addition to their lipid-lowering effects, HMG-CoA reductase inhibitors (statins) induce a variety of pleiotropic actions that have been recently studied in the area of cardiovascular and renal protection. In the present studies we sought to determine whether statins retain beneficial effects in the experimental model of NO deficiency achieved by chronic administration of a pressor dose of L-arginine analogue N-nitro-L-arginine-methyl ester (L-NAME). METHODS: To address this issue, blood pressure (BP), renal function (GFR), and albuminuria were determined in rats treated for 4 weeks with L-NAME, L-NAME + atorvastatin (ATO), and in untreated controls. In addition, renal cortical protein expression of caveolin 1 (CAV1), vascular endothelial growth factor (VEGF), and activity of RhoA were also determined. RESULTS: L-NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria as compared to control animals. Co-administration of ATO with L-NAME normalized albuminuria and prevented decreases in GFR in L-NAME rats without having an impact on pressor effects of L-NAME. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L-NAME-treated animals, and normalized with co-administration of ATO. CONCLUSION: Treatment with ATO exerts early nephroprotective effects in the NO-deficient model of hypertension. These effects could be mediated by amelioration of VEGF expression and reduction of RhoA activity.

Albuminuria↗

PubMed2006

Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney.

Experimental diabetes is associated with complex changes in renal nitric oxide (NO) bioavailability. We explored the effect of diabetes on renal cortical protein expression of endothelial NO synthase (eNOS) with respect to several determinants of its enzymatic function, such as eNOS expression, membrane localization, phosphorylation, and dimerization, in moderately hyperglycemic streptozotocin-induced diabetic rats compared with nondiabetic control rats and diabetic rats with intensive insulin treatment to achieve near-normal metabolic control. We studied renal cortical expression and localization of caveolin-1 (CAV-1), an endogenous modulator of eNOS function. Despite similar whole-cell eNOS expression in all groups, eNOS monomer and dimer in membrane fractions were reduced in moderately hyperglycemic diabetic rats compared with control rats; the opposite trend was apparent in the cytosol. Stimulatory phosphorylation of eNOS (Ser1177) was also reduced in moderately hyperglycemic diabetic rats. eNOS colocalized and interacted with CAV-1 in endothelial cells throughout the renal vascular tree both in control and moderately hyperglycemic diabetic rats. However, the abundance of membrane-localized CAV-1 was decreased in diabetic kidneys. Intensive insulin treatment reversed the effects of diabetes on each of these parameters. In summary, we observed diabetes-mediated alterations in eNOS and CAV-1 expression that are consistent with the view of decreased bioavailability of renal eNOS-derived NO.

Animals↗

PubMed2005

Renal cyclooxygenase-2 in obese Zucker (fatty) rats.

BACKGROUND: Cyclooxygenase (COX) isoforms, COX-1 and COX-2, are involved in production of prostanoids in the kidney. Increases in renal COX-2 expression have been implicated in the pathophysiology of progressive renal injury, including type 1 diabetes. Thromboxane A(2) (TxA(2)) has been suggested as the key mediator of these effects resulting in up-regulation of prosclerotic cytokines and extracellular matrix proteins. Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes. METHODS: Renal cortical COX protein expression, and urinary excretion of stable metabolites of prostaglandin E(2) (PGE(2)) and TxA(2), in association with metabolic parameters, were determined in 4-and 12-week-old Zucker fatty rats (fa/fa rat) (ZDF4 and ZDF12), a model of type 2 diabetes, and in age-matched littermates with no metabolic defect (Zucker lean) (ZL4 and ZL12). RESULTS: Western blotting revealed increased COX-2 expression in ZDF4 as compared to ZL4 (245 +/- 130%) (P < 0.05). This increase in COX-2 was even more apparent in 12-week-old ZDF rats (650 +/- 120%) (P < 0.01). All groups of rats demonstrated COX-2-positive cells in typical cortical localizations [macula densa, thick ascending loop of Henle (TALH)]. In contrast to COX-2, COX-1 expression was 30% lower in ZDF12. These changes in COX expression were associated with enhanced urinary excretion of prostanoids, in parallel with the development of metabolic abnormalities. Moreover, increases in prostanoid excretion in ZDF12 were in part reduced by wortmannin (100 mug/kg), used as inhibitor of insulin signaling. CONCLUSION: Renal cortical COX-2 protein expression and function were increased in ZDF rats, as compared to controls, whereas COX-1 exhibited opposite regulation. The changes in COX-2 paralleled metabolic abnormalities, and were at least in part a four consequence of hyperinsulinemia. These abnormalities may play a role in renal pathophysiology in this model of type 2 diabetes.

Androstadienes↗

PubMed2005

Gender hormones and the progression of experimental polycystic kidney disease.

BACKGROUND: Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. METHODS: Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. RESULTS: Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. CONCLUSION: Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Androgens↗

PubMed2004

Acute effects of cyclooxygenase-2 inhibition on renal function in heterozygous ren-2-transgenic rats on normal or low sodium intake.

BACKGROUND/AIMS: Since there are no data available so far on the role of renal cyclooxygenase-2 (COX-2) in hypertensive Ren-2-transgenic rats (TGR), in the present study we evaluated renal cortical COX-2 protein expression and prostaglandin E2 (PGE2) concentrations as well as renal functional responses to acute COX-2 inhibition in male heterozygous TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats fed either a normal-sodium (NS) or a low-sodium (LS) diet. METHODS: In rats fed either the NS or the LS diet for 12 days and prepared for clearance experiments with left ureteral catheterization, the renal functional responses of the left kidney were evaluated after intrarenal COX-2 inhibition with DuP-697 or NS-398. In renal cortical tissue, COX-2 protein expression was assessed by immunoblotting, and the concentration of PGE2 as a marker of COX-2 activity was determined by enzyme immunoassay. Mean arterial pressure in the right femoral artery was monitored by means of a pressure transducer. RESULTS: In heterozygous TGR, to our surprise, the LS diet normalized the mean arterial pressure. Despite significantly higher renocortical expression of COX-2 and PGE2 concentrations as well as urinary PGE2 excretion in TGR as compared with HanSD rats kept on the NS diet, selective intrarenal COX-2 inhibition did not influence renal function either in TGR or in HanSD rats. The LS diet increased renocortical COX-2 expression and PGE2 concentrations as well as urinary PGE2 excretion significantly stronger in TGR than in HanSD rats. Regardless of these increases, the intrarenal COX-2 inhibition caused comparable decreases in glomerular filtration rate, in absolute and fractional sodium excretion, as well as in urinary PGE2 excretion in TGR and HanSD rats kept on the LS diet. CONCLUSIONS: The present data show that a LS diet normalizes the mean arterial pressure in heterozygous male TGR. This first study on the role of renal COX-2 in TGR also demonstrates that COX-2-derived vasodilatory prostanoids do not act as renal compensatory vasodilator and natriuretic substances in this model of hypertension.

Animals↗

PubMed2004

Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats.

Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodynamic changes in diabetes mellitus (DM). However, the role of NO in the pathophysiology of diabetic nephropathy remains controversial. Renal hemodynamic changes in experimental DM can be acutely normalized by selective inhibition of neuronal NO synthase (nNOS). This observation suggests a nephroprotective potential of nNOS inhibition in DM. To explore this issue we assessed the long-term effects (12 weeks) of selective nNOS inhibition with the specific inhibitor S-methyl-L-thiocitrulline (SMTC) in uninephrectomized control and streptozotocin-diabetic rats. No beneficial effects of SMTC were observed in nondiabetic controls. In contrast, SMTC delayed the development of proteinuria (32+/-8 vs. 53+/-9 mg/24h, week 8, p < 0.05) and glomerulosclerosis (GS, 0.30+/-0.08 vs. 0.57+/-0.05, p < 0.05) in diabetic rats. These effects coincided with early effects of treatment on the glomerular filtration rate, and were associated with lower renal expression of nNOS. Furthermore, SMTC-treated diabetic rats demonstrated reduced weight gain and urinary sodium excretion as compared to vehicle-treated counterparts, despite similar metabolic control and blood pressure. In summary, long-term nNOS inhibition had modest nephroprotective effects in uninephrectomized diabetic rats. These effects may be mediated by renal hemodynamic mechanisms, as well as by lower food (protein) intake.

Animals↗

PubMed2004

Effects of ACE inhibition and AT1-receptor blockade on haemodynamic responses to L-arginine in Type 1 diabetes.

INTRODUCTION: Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve endothelial function in Type 1 diabetes. However, the potential of ACE inhibitors (ACE-I) to enhance the haemodynamic effects of L-arginine (L-arg), the precursor of nitric oxide (NO), has not been evaluated. Furthermore, angiotensin receptor blockers (ARBs), another group of inhibitors of the renin-angiotensin system (RAS), have not been studied in this context. METHODS: Using a randomised, crossover design, the acute effects of L-arg (200 mg/kg) on blood pressure (BP) and renal haemodynamics were determined in uncomplicated Type 1 diabetic patients before and after three weeks of treatment with the ACE-I ramipril (5 mg/day) or the ARB losartan (50 mg/day). RESULTS: L-arg alone did not influence BP or renal haemodynamics. BP responses to L-arg were not modulated by ACE-I or ARB. In contrast to the systemic responses, L-arg induced significant renal vasodilation after treatment with ramipril (p<0.05). Unlike ramipril, losartan did not modulate renal haemodynamic responses to L-arg. L-arg administration was paralleled by increments in plasma L-citrulline levels, determined as a measure of L-arg-induced systemic NO production. These responses were not influenced by RAS inhibitors. No changes in other indicators of the systemic and renal NO production, such as plasma and urinary nitrates/nitrites, were detected in response to L-arg alone or after treatment with RAS inhibitors. CONCLUSIONS: ACE-Is have greater potential than ARBs to enhance L-arg effects in the kidney in uncomplicated Type 1 diabetes. Neither RAS inhibitor influenced the systemic effects of L-arg. The lack of changes in renal NO indicators parallelling the haemodynamic responses, suggests that the effects of ACE-I on L-arg-induced renal haemodynamic changes could be also attributable to NO-independent mechanisms.

Adult↗

PubMed2003

Endothelial-derived vasoactive mediators in polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by hypertension and renal vasoconstriction. Mediators of these hemodynamic changes are not well understood, but evidence suggests that endothelial-derived mediators may participate. METHODS: Baseline measurements of blood pressure, proteinuria, and urinary nitrite/nitrate excretion were performed in control and cystic male Han:SPRD rats (6 weeks of age). They were then treated with the nitric oxide (NO), nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or vehicle, for 6 weeks. After repeat systemic measurements, renal function was determined using inulin and para-aminohippurate (PAH) clearances. Levels of renal endothelin-1 (ET-1) and renal endothelial NOS (eNOS) proteins were determined, and immunohistochemistry localized renal eNOS and neuronal NOS (nNOS). RESULTS: Administration of L-NAME aggravated systemic hypertension and renal vasoconstriction in the cystic rats, but did not affect the progression of proteinuria or cystic expansion. Cystic rats demonstrated marked increases in renal ET-1 and eNOS levels. L-NAME reduced eNOS expression in the membrane compartment, but increased eNOS in the cytosol. Localization studies indicated that renal eNOS was abundant in nonvascular compartments, but not in renal vascular and glomerular structures, whereas renal nNOS was diffusely diminished. CONCLUSION: These alterations of endothelial-derived mediators (up-regulation of ET-1, and dysfunction of the NO system) contribute to vasoconstriction, and thereby are likely to contribute to the progressive loss of renal function in polycystic kidney disease (PKD).

Animals↗

PubMed2003

Paradoxes of nitric oxide in the diabetic kidney.

As an important modulator of renal function and morphology, the nitric oxide (NO) system has been extensively studied in the diabetic kidney. However, a number of studies in different experimental and clinical settings have produced often confusing data and contradictory findings. We have reviewed a wide spectrum of findings and issues that have amassed concerning the pathophysiology of the renal NO system in diabetes, pointed out the controversies, and attempted to find some explanation for these discrepancies. Severe diabetes with profound insulinopenia can be viewed as a state of generalized NO deficiency, including in the kidney. However, we have focused our hypotheses and conclusions on the events occurring during moderate glycemic control with some degree of treatment with exogenous insulin, representing more the clinically applicable state of diabetic nephropathy. Available evidence suggests that diabetes triggers mechanisms that in parallel enhance and suppress NO bioavailability in the kidney. We hypothesize that during the early phases of nephropathy, the balance between these two opposing forces is shifted toward NO. This plays a role in the development of characteristic hemodynamic changes and may contribute to consequent structural alterations in glomeruli. Both endothelial (eNOS) and neuronal NO synthase can contribute to altered NO production. These enzymes, particularly eNOS, can be activated by Ca(2+)-independent and alternative routes of activation that may be elusive in traditional methods of investigation. As the duration of exposure to the diabetic milieu increases, factors that suppress NO bioavailability gradually prevail. Increasing accumulations of advanced glycation end products may be one of the culprits in this process. In addition, this balance is continuously modified by actual metabolic control and the degree of insulinopenia.

Animals↗

PubMed2002

Effects of cyclooxygenase-2 (COX-2) inhibition on plasma and renal renin in diabetes.

COX-2-derived prostaglandins (PG) have been suggested to be important modulators of renin release and expression. However, the role of COX-2 in various high-renin states is still being debated. In the present studies we explored the role of COX-2-derived PG on basal and angiotensin converting enzyme inhibitor (ACEI)-stimulated plasma and renal renin concentrations (PRC and RRC, RIA), and mRNA expression (RmRNA, RNAse protection assay) in experimental diabetes (DM). Groups of moderately hyperglycemic (n = 5, approximately 350 mg/dl), streptozotocin-diabetic rats (D) after 3 weeks of DM were treated with a selective COX-2 inhibitor, MF-tricyclic (MF, 5 mg/kg/day for 10 days in food), the combination of MF and the ACEI enalapril (3 mg/kg/day), enalapril alone, or vehicle (MF-free chow), for 10 days. Non-diabetic control rats, fed MF-free chow, were also studied. All groups of diabetic rats demonstrated similar glycemic control. Treatment with ACEI resulted in significant elevations in PRC, RRC and RmRNA as compared to non-ACEI treated groups of diabetic and control rats. A similar rise in these parameters was observed in the rats treated with the combination of ACEI and MF. Furthermore, in diabetic rats treated with MF alone, PRC and RRC were similar to vehicle-treated animals. Diabetic rats demonstrated higher urinary PG as compared to controls. MF-treated rats demonstrated a significant reduction in urinary PG excretion. In summary, selective COX-2 inhibition influenced neither basal renin status nor ACEI-induced renin release and expression in diabetic rats. These findings do not support a significant role for COX-2 in mediating renin status in diabetes.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Cyclooxygenase-2 expression and function in renal pathophysiology.

Cyclooxygenase (COX) constitutes the rate-limiting enzyme in the biosynthetic cascade of prostaglandin (PG). Evidence has accrued suggesting pathophysiological states with altered COX-2 activity and expression. Recent experimental evidence suggests that COX-2 has a pathogenetic role in some of these derangements. In other situations, the effect of altered COX-2 regulation is unclear or possibly beneficial. These processes suggest new areas for potential use of COX-2-specific inhibitors. Conversely, in some conditions COX-2-specific inhibitors should be avoided. The conventional view is that COX-2 is an inducible enzyme. However, COX-2 is also active in the constitutive production of prostanoids in the kidney. Consequently, the pathophysiological states discussed herein include not only COX-2 induction during inflammation but also derangements in COX-2 expression and function caused by non-inflammatory stimuli.

Animals↗

PubMedDate not supplied

Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats.

1. Cyclo-oxygenase (COX)-2 is involved in constitutive production of prostanoids in the kidney and plays a role in the control of renal function and morphology. Renal cortical COX-2 expression and function is increased in experimental models of diabetes (DM). However, pathophysiological roles of this phenomenon in the diabetic kidney have not been fully elucidated. To address this issue, we studied the nephroprotective potential of long-term (16 weeks) COX-2 inhibition in uninephrectomized streptozotocin-diabetic rats (D). 2. Diabetic rats received either a low or high dose of the selective COX-2 inhibitor MF-tricyclic (MF; 1 or 5 mg/kg per day in chow). Another group of D rats received high-dose MF as late intervention starting at 8 weeks of DM (D-MFlate). The effects of treatments were compared with age-matched uninephrectomized diabetic and non-diabetic rats receiving drug-free chow (D-VE and C-VE, respectively). 3. No differences in blood pressure and metabolic control were observed between groups of D rats throughout the study. The D-VE group developed progressive albuminuria and glomerulosclerosis, associated with increased excretion of the thromboxane (TX) A(2) metabolite TxB(2). Treatment with MF attenuated albuminuria in diabetic rats with late intervention, but not in D rats treated with MF from the onset of DM. Moreover, D-MFlate rats demonstrated a significant reduction in the development of glomerulosclerosis. These effects coincided with prevention of diabetes-induced rise in urinary TxB(2) excretion. 4. In conclusion, long-term COX-2 inhibition is associated with modest nephroprotection in uninephrectomized diabetic rats when administered as late intervention. These effects are independent of metabolic control and blood pressure.

Albuminuria↗