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ABSTRACT: We examined the production of prostaglandin (P0) E2, 6-keto PGF1α and thromboxane (Tx) B2, the mass of cyclooxygenase (COX) isoenzymes and the activities of phospholipases A2 and C in glomeruli, cortical tubules and medullary tubules of rat kidneys. Medullary tubules produced significantly greater amounts of PGE2, 6-keto PGF1α. and TxB2 than glomeruli or cortical tubules. the most abundant eicosanoid in medullary tubules was 6-keto PGF1α. By contrast, glomeruli and cortical tubules predominantly produced POE2 (glomeruli > cortical tubules). Levels of COX 1 were markedly greater in medullary tubules than in glomeruli or cortical tubules. Glomeruli had significantly greater amounts of COX 1 than cortical tubules. Detectable amounts of COX 2 were not present in the three preparations. the activity of phospholipase (PL) A2 against phosphatidyicholine (PC) was significantly greater in tubules (medullary tubules > cortical tubules) than in glomeruli. By contrast, there was a significant increase in the activity of PLA2 against phosphatidylethanolamine (PE) in glomeruli as compared to tubules (medullary tubules > cortical tubules). the activity of PLC was the Weatest in medullary tubules. Glomeruli had significantly greater activity of PLC than cortical tubules. the order of magnitude for the total activity of the three phospholipases in membranes was medullary tubules> glomeruli> cortical tubules. the total production rate of POE2, 6-keto PGF1α and TxB2 was in parallel with the amount of COX 1 and the total activity of membranous phospholipases A2 and C in the three preparations. In conclusion, there are differences in the production of PGE2, 6.-keto PGF1α and TxB2, the ainount of COX 1 and the activities of phospholipases A2 andC among glomeruli, cortical tubules and medullary tubules of rat kidneys; and the different aspects of COX 1 and phospholipases A2 and C have a key role in the control of eicosanoid production in the three preparations.
Nephrology 04/2007; 1(1):31 - 38. · 1.31 Impact Factor
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Vicente E Torres,
Bernard F King,
Arlene B Chapman,
Marijn E Brummer,
Kyongtae T Bae,
James F Glockner,
Kraisthith Arya,
Dana Risk,
Joel P Felmlee,
Jared J Grantham,
Lisa M Guay-Woodford,
William M Bennett, Saulo Klahr,
Catherine M Meyers,
Xiaoling Zhang,
Paul A Thompson,
J Philip Miller
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ABSTRACT: Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.
Clinical Journal of the American Society of Nephrology 02/2007; 2(1):112-20. · 5.23 Impact Factor
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Peter C Harris,
Kyongtae T Bae,
Sandro Rossetti,
Vicente E Torres,
Jared J Grantham,
Arlene B Chapman,
Lisa M Guay-Woodford,
Bernard F King,
Louis H Wetzel,
Deborah A Baumgarten,
Philip J Kenney,
Mark Consugar, Saulo Klahr,
William M Bennett,
Catherine M Meyers,
Qin Jean Zhang,
Paul A Thompson,
Fang Zhu,
J Philip Miller
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ABSTRACT: Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.
Journal of the American Society of Nephrology 12/2006; 17(11):3013-9. · 9.66 Impact Factor
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Jared J Grantham,
Vicente E Torres,
Arlene B Chapman,
Lisa M Guay-Woodford,
Kyongtae T Bae,
Bernard F King,
Louis H Wetzel,
Deborah A Baumgarten,
Phillip J Kenney,
Peter C Harris, Saulo Klahr,
William M Bennett,
Gladys N Hirschman,
Catherine M Meyers,
Xiaoling Zhang,
Fang Zhu,
John P Miller
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ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys.
In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis.
Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (+/-SD) total kidney volume was 1060+/-642 ml at baseline and increased by a mean of 204+/-246 ml (5.27+/-3.92 percent per year, P<0.001) over a three-year period among 214 patients. Total cyst volume increased by 218+/-263 ml (P<0.001) during the same period among 210 patients. The baseline total kidney volume predicted the subsequent rate of increase in volume, independently of age. A baseline total kidney volume above 1500 ml in 51 patients was associated with a declining glomerular filtration rate (by 4.33+/-8.07 ml per minute per year, P<0.001). Total kidney volume increased more in 135 patients with PKD1 mutations (by 245+/-268 ml) than in 28 patients with PKD2 mutations (by 136+/-100 ml, P=0.03).
Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function.
New England Journal of Medicine 06/2006; 354(20):2122-30. · 53.30 Impact Factor
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Andrew D Rule,
Vicente E Torres,
Arlene B Chapman,
Jared J Grantham,
Lisa M Guay-Woodford,
Kyongtae T Bae, Saulo Klahr,
William M Bennett,
Catherine M Meyers,
Paul A Thompson,
J Philip Miller
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ABSTRACT: A decline in renal function suggests progression of chronic kidney disease. This can be determined by measured GFR (e.g., iothalamate clearance), serum creatinine (SCr)-based GFR estimates, or creatinine clearance. A cohort of 234 patients with autosomal dominant polycystic kidney disease and baseline creatinine clearance>70 ml/min were followed annually for four visits. Iothalamate clearance, SCr, and creatinine clearance were obtained at each visit. Estimated GFR (eGFR) was determined with the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Renal function slopes had a mean residual SD of 10.7% by iothalamate clearance, 8.2% by MDRD equation, 7.7% by Cockcroft-Gault equation, and 14.8% by creatinine clearance. By each method, a decline in renal function (lowest quintile slope) was compared among baseline predictors. Hypertension was associated with a decline in iothalamate clearance (odds ratio [OR] 5.8; 95% confidence interval [CI] 2.3 to 14), eGFR (OR [MDRD] 2.0 [95% CI 1.0 to 4.2] or OR [Cockcroft-Gault] 1.9 [95% CI 0.9 to 3.9]), and creatinine clearance (OR 2.0; 95% CI 1.0 to 4.2). Each doubling of kidney volume at baseline was associated with a decline in iothalamate clearance (OR 2.4; 95% CI 1.5 to 3.7), eGFR (OR 1.7 [95% CI 1.1 to 2.6] or 2.1 [95% CI 1.4 to 3.3]), and creatinine clearance (OR 1.7; 95% CI 1.1 to 2.5). Predictor associations were strongest with measured GFR. Misclassification from changes in non-GFR factors (e.g., creatinine production, tubular secretion) conservatively biased associations with eGFR. Misclassification from method imprecision attenuated associations with creatinine clearance.
Journal of the American Society of Nephrology 03/2006; 17(3):854-62. · 9.66 Impact Factor
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Kyongtae T Bae,
Fang Zhu,
Arlene B Chapman,
Vicente E Torres,
Jared J Grantham,
Lisa M Guay-Woodford,
Deborah A Baumgarten,
Bernard F King,
Louis H Wetzel,
Philip J Kenney,
Marijn E Brummer,
William M Bennett, Saulo Klahr,
Catherine M Meyers,
Xiaoling Zhang,
Paul A Thompson,
J Philip Miller
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ABSTRACT: The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.
Clinical Journal of the American Society of Nephrology 02/2006; 1(1):64-9. · 5.23 Impact Factor
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ABSTRACT: Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.
Seminars in Nephrology 08/2004; 24(4):389-94. · 2.12 Impact Factor
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ABSTRACT: The nephropathy induced by ureteral obstruction is associated with increased interstitial volume due to matrix deposition, fibroblast differentiation/proliferation, and monocyte infiltration. Recent studies indicate that transforming growth factor-beta (TGF-beta) is linked to renal fibrosis. Tumor necrosis factor (TNF-alpha) has a role in the recruitment of inflammatory cells. We found that infiltration of macrophages of the interstitium in unilateral ureteral obstruction (UUO) occurred as early as four hours after the onset of UUO.
Recent studies indicate that a renal tubular development morphogen, bone morphogenetic protein-7 (BMP-7), is effective in preventing the tubulointerstitial nephritis in the setting of obstructive nephropathy. The mechanism of action appears to be preservation of epithelial cell phenotype, inhibition of epithelial-mesenchymal transdifferentiation, and inhibition of injury-induced epithelial cell apoptosis. Hepatocyte growth factor (HGF) also inhibited tubulointerstitial fibrosis.
In a treatment protocol in rats with ureteral ligation, BMP-7 restored renal function. The preservation of glomerular filtration rate (GFR) was accompanied by a significant decrease in cortical interstitial volume. In diabetic rats given BMP-7 proteinuria was normalized. In mice with ureteral obstruction, HGF suppressed the expression of TGF-beta and of platelet-derived growth factor. The onset of tubulointerstitial fibrosis was almost completely inhibited by HGF.
Both BMP-7 and HGF attenuate the tubulointerstitial fibrosis due to ureteral obstruction. They also increase GFR and renal plasma flow.
Kidney international. Supplement 12/2003;
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Bernard F King,
Vicente E Torres,
Marijn E Brummer,
Arlene B Chapman,
Kyongtae T Bae,
James F Glockner,
Kraisthith Arya,
Joel P Felmlee,
Jared J Grantham,
Lisa M Guay-Woodford,
William M Bennett, Saulo Klahr,
Gladys H Hirschman,
Paul L Kimmel,
Paul A Thompson,
J Phillip Miller
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ABSTRACT: Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention.
Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding.
Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments.
Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD.
Kidney International 12/2003; 64(6):2214-21. · 6.61 Impact Factor
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Arlene B Chapman,
Lisa M Guay-Woodford,
Jared J Grantham,
Vicente E Torres,
Kyongtae T Bae,
Deborah A Baumgarten,
Philip J Kenney,
Bernard F King,
James F Glockner,
Louis H Wetzel,
Marijn E Brummer,
W Charles O'Neill,
Michelle L Robbin,
William M Bennett, Saulo Klahr,
Gladys H Hirschman,
Paul L Kimmel,
Paul A Thompson,
J Philip Miller
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ABSTRACT: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease.
Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations.
Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion.
MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.
Kidney International 09/2003; 64(3):1035-45. · 6.61 Impact Factor
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ABSTRACT: Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD).
Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 microg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured.
Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 +/- 0.02 mL/min/100 g body weight vs. 0.55 +/- 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 +/- 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 +/- 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels.
BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.
Kidney International 07/2003; 63(6):2037-49. · 6.61 Impact Factor
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ABSTRACT: Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.
American Journal of Kidney Diseases 04/2003; 41(3 Suppl 1):S3-7. · 5.43 Impact Factor
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ABSTRACT: Angiotensin II (Ang II) regulates a number of genes associated with progression of renal disease. The regulation of gene expression by Ang II occurs through specific receptors that are linked to changes in the activity of transcription factors within the nucleus of target cells. In particular, members of the nuclear factor-kappaB family of transcription factors are activated, which in turn fuels at least two autocrine reinforcing loops that amplify Ang II and tumor necrosis factor-alpha formation. Angiotensin converting enzymes (ACE) inhibitors and angiotensin antagonists (AIIAs) differ both pharmacokinetically and pharmacodynamically in patients with end-stage renal disease (ESRD). Several ACE inhibitors (such as captopril, enalapril and lisinopril) are dialyzable, whereas all of the AIIAs studied are not. Dose titration may be necessary when administering ACE inhibitors to patients with renal failure (ESRD), but is rarely a consideration when AIIAs are used.
Kidney international. Supplement 01/2003;
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ABSTRACT: Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ET(B) receptor.
American journal of physiology. Renal physiology 01/2003; 284(1):F209-17. · 3.68 Impact Factor
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ABSTRACT: Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.
American journal of physiology. Renal physiology 12/2002; 283(5):F861-75. · 3.68 Impact Factor
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ABSTRACT: Harvey Lester White (1896-1977) graduated from Washington University (St. Louis) School of Medicine and subsequently spent his entire professional career in the School's Department of Physiology. White's interest in the function of the kidney was evident early in his academic career when he pioneered research related to renal physiology. His first papers dealt with studies of renal tubular function (1923). He performed what appear to represent the first micropuncture studies in the kidney of Necturus maculosus (1926) and thus confirmed the observations of Wearn and Richards regarding glomerular filtration. Through these studies, he was the first to show that glucose reabsorption occurs in the proximal tubules of Necturus. It also appears that White et al. were the first to demonstrate that volume expansion increases bicarbonate excretion in dogs (1926). He studied the influence of posture on renal "activity" in man (1926). Intracapsular pressure determinations in Necturus kidney (1928) were done using micropuncture techniques. White and co-workers presented (1933) a comparison of clearances of creatinine and various sugars confirming the work of Jolliffe, Shannon and Smith (1932) who had proposed the clearances of non-metabolizable sugars to be a measure of glomerular filtration. Between 1932 and 1936, in an effort to better understand the process of glomerular filtration, he began a series of studies on streaming potentials, surface conductance, electro-endosmosis and other related topics. In 1937, White began work on yet another aspect of renal physiology--endocrine influences on renal function. He would immerse himself in these investigations throughout the remainder of his scientific career. We hope that this account will reveal at least a small dimension of the man and his contributions to renal physiology.
American Journal of Nephrology 08/2002; 22(2-3):180-5. · 2.54 Impact Factor
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ABSTRACT: For elucidation of the mechanisms by which growth factors and cytokines affect renal epithelial cells, gene array analysis of renal cells cultured in the presence of transforming growth factor-beta1 (TGF-beta1) was performed. Many genes that were not previously considered to be involved in renal cell biologic processes were affected, one of which was jagged-1. The jagged ligand/notch receptor family controls the formation of boundaries between groups of cells and regulates cell fates. On the basis of the array analysis, jagged-1 expression was further evaluated in cultured cells and in C57BL/6 mice with a model of unilateral ureteral obstruction (UUO). Recombinant human TGF-beta1 increased jagged-1 mRNA levels at concentrations between 10(-11) and 10(-10) M. There was a commensurate increase in jagged-1 protein levels, as assessed by Western blotting. The expression of jagged-1 mRNA and protein was observed to be significantly increased in the kidneys of C57BL/6 mice with obstructed ureters, compared with the contralateral kidneys, at 7 and 14 d of UUO. Immunohistochemical analyses demonstrated jagged-1 expression in distal tubules of kidneys from normal mice or contralateral kidneys from mice with UUO. Jagged-1 protein expression was increased in tubules not yet in apparent atrophy in the kidneys with an obstructed ureter. Jagged-1 expression was significantly increased in the kidneys of normal mice treated with TGF-beta1 and was decreased in the kidneys of mice with UUO treated with a TGF-beta receptor II-Fc chimera. These results suggest that jagged-1 is expressed in normal kidneys and that this expression is upregulated during renal disease, in a TGF-beta-dependent manner.
Journal of the American Society of Nephrology 07/2002; 13(6):1499-508. · 9.66 Impact Factor
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ABSTRACT: The molecular cloning of many bone morphogenetic proteins (BMP)-encoding genes and their identification as transforming growth factor-beta (TGF-beta) relatives enhanced the interest in these molecules and allowed expression and functional studies to be performed.
Rats with ureteral obstruction were distributed into four groups. Group 1 received vehicle, group 2 received enalapril 12.5 mg/kg body wt/day, group 3 received 50 or 300 microg/kg body wt BMP-7, and group 4 received both enalapril and the high dose of BMP-7. We also studied the effects of BMP-7 administration in a model streptozocin-induced diabetes.
Treatment with BMP-7 in rats with ureteral obstruction of 3 days duration and subsequent release indicated that this compound decreases interstitial volume and accelerates the return of renal function. After 16 weeks of diabetes, the rats were treated with BMP-7. The administration of BMP-7 partially reversed renal hypertrophy, restored GFR to normal, and decreased proteinuria.
These studies indicate that administration of BMP-7 maintains and restores renal function and structure in animals with ureteral obstruction and diabetic nephropathy.
Kidney international. Supplement 06/2002;
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ABSTRACT: A prevention protocol has demonstrated that bone morphogenetic protein-7 (BMP-7) blunted the development of fibrosis in a rat model of unilateral ureteral obstruction. This prevention protocol also preserved, to an extent, renal function. The prevention protocol was extended and a treatment protocol used to examine if BMP-7 was beneficial at limiting fibrosis of the kidney when the BMP-7 was administered during the progression of fibrotic disease. Animals were distributed into four groups. Group 1 received vehicle, group 2 received enalapril (12.5 mg/kg body wt per d), group 3 received BMP-7 (50 or 300 microg/kg), and group 4 received both the enalapril and the high dose of BMP-7. Rats underwent reversible unilateral ureteral obstruction for 3 d, after which the obstruction was relieved. In the treatment protocol, 300 microg/kg BMP-7 was given after the release of obstruction. Seven days after release of the obstruction and the onset of treatment glomerular filtration rate (GFR), renal blood flow, and various histologic indexes of fibrosis were determined. On a consistent basis, BMP-7 treatment alone was found to be slightly but significantly (P < 0.04 to 0.007) better than enalapril alone or in combination with enalapril at decreasing interstitial volume or tubule atrophy. BMP-7 treatment was slightly but not significantly better (P < 0.09) than enalapril at restoring GFR in the prevention protocol. Treatment with BMP-7 significantly boosted GFR (P < 0.01) above that seen with vehicle treatment. These results suggest that BMP-7 treatment is capable of blunting the progression of fibrotic disease and of decreasing interstitial volume. Importantly, a return of renal function is accelerated by BMP-7 treatment. These results suggest that administration of BMP-7 may be an effective treatment to restore or preserve renal histology and renal function in this experimental model of renal disease.
Journal of the American Society of Nephrology 01/2002; 13 Suppl 1:S14-21. · 9.66 Impact Factor
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ABSTRACT: Protein increases glomerular eicosanoid production and activity of related enzymes. We examined the in vitro production of PGE2, 6-keto PGF1 and TxB2 by isolated glomeruli from rats fed a low (6% casein) or a high (40% casein) protein diet for approximately eight weeks. Glomeruli from high protein-fed rats produced significantly greater amounts of PGE2, 6-keto PGF1 and TxB2 under basal conditions and in response to the addition of 100 nM angiotensin II (Ang II) than glomeruli from low protein-fed rats. To elucidate the mechanisms by which greater protein intake enhanced the glomerular production of eicosanoids, we explored phospholipase (A2 and C) and cyclooxygenase activity in glomeruli isolated from low- or high-protein fed rats. PE-specific PLA2 activities were significantly increased in glomeruli from rats fed a high protein diet when compared to a low protein diet. On the other hand, PC-specific PLA2 activities were significantly decreased in glomeruli from rats fed a high protein diet. No significant difference in PIP2-PLC activities was detected between glomeruli of the two dietary groups. The cyclooxygenase content and activity was significantly greater in glomeruli from rats fed a high protein diet than in glomeruli from rats fed a low protein diet. Glomeruli of rats fed a 50/50 mixture of the diets (23% casein) had amounts and activity of cyclooxygenase and activities of PE-specific PLA2 intermediate between those of high and low protein-fed animals. In conclusion, increased synthesis of ei-cosanoids by glomeruli from rats fed a high protein diet may be mediated by increases in the amount and activity of cyclooxygenase coupled with enhanced activity of PE-specific PLA2.
Kidney International 05/1992; 41(4). · 6.61 Impact Factor
