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ABSTRACT: Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.
AJP Renal Physiology 09/2011; 302(1):F141-9. · 4.42 Impact Factor
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Kidney international. Supplement 02/2011;
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Eduardo Slatopolsky
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ABSTRACT: Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the 'intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that 'as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca²+ and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca²+ sensing receptor, and Klotho-fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an 'intestinal phosphatonin'. These observations suggest a possible 'phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-α-epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function.
Kidney international. Supplement 02/2011;
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ABSTRACT: Vascular calcification is a major contributor to morbidity and mortality in hemodialysis. The objective of this pilot study was to determine the feasibility, safety and efficacy of sodium thiosulfate (STS) in the progression of vascular calcification in hemodialysis patients.
Chronic hemodialysis patients underwent a battery of cardiovascular tests. Those with coronary artery calcium (Agatston scores >50) received intravenous STS after each dialysis for 5 months (n = 22) and the tests were repeated. Changes in MDCT-determined calcification were assessed as the mean annualized rate of change in 3 vascular beds (coronary, thoracic and carotid arteries) and in L1-L2 vertebral bone density.
Although individual analyses showed coronary artery calcification progression in 14/22 subjects, there was no progression in the mean annualized rate of change of vascular calcification in the entire group. The L1-L2 vertebral bone density showed no changes. There were no correlations between rates of progression of vascular calcification and phosphorus, fetuin or C-reactive protein levels. Changes in coronary artery calcification scores correlated with those of the thoracic aorta.
STS treatment is feasible, appears safe and may decrease the rate of progression of vascular calcification in hemodialysis patients. A large, randomized, controlled trial is warranted.
American Journal of Nephrology 01/2011; 33(2):131-8. · 2.54 Impact Factor
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ABSTRACT: Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Traditional causes such as diabetes, smoking, aging and hypertension do not fully explain the high rate of morbidity from cardiovascular disease seen in these patients. The renin-angiotensin-aldosterone system (RAAS) regulates extracellular volume homeostasis, which contributes to blood pressure stability. Overactivity of this system is involved in the pathophysiology of cardio-renal disease. New evidence suggests that vitamin D receptor activators (VDRAs) have a suppressive effect on the RAAS; however, VDRAs also have anti-inflammatory and anti-fibrotic effects. We have demonstrated that paricalcitol, a VDRA, ameliorates left ventricular hypertrophy (LVH) in uremic rats by up-regulating the VDR, decreasing myocardial PCNA and also decreasing myocardial oxidative stress. Thus, paricalcitol can suppress the progression of LVH, myocardial and perivascular fibrosis and myocardial arterial vessel thickness presumably by up-regulating the VDR. Paricalcitol may prove to have a substantial beneficial effect on cardiac disease and its outcome in patients with CKD. Prospective randomized studies in CKD patients are necessary to confirm these results.
The Journal of steroid biochemistry and molecular biology 03/2010; 121(1-2):188-92. · 2.66 Impact Factor
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ABSTRACT: Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.
AJP Renal Physiology 03/2010; 298(6):F1315-22. · 4.42 Impact Factor
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ABSTRACT: Left ventricular hypertrophy (LVH) is the most frequent cardiac complication in chronic renal disease. Previous studies implicate elevated serum phosphorus as a risk factor for LVH.
We treated 5/6 nephrectomized rats with enalapril or enalapril + sevelamer carbonate for 4 months to determine if sevelamer carbonate had an additional beneficial effect on the development of LVH and uremia-induced left ventricle (LV) remodeling.
Uremia increased LV weight and cardiomyocyte size. Enalapril and enalapril + sevelamer blunted the increase in left ventricular weight. Only enalapril + sevelamer diminished the increase in cardiomyocyte size. Uremia increased cyclin D2 and PCNA and decreased p27 protein expression in the heart. Enalapril + sevelamer diminished the decrease in p27 expression caused by uremia. Uremia increased Ki67-positive and phosphohistone H(3)-positive interstitial cells. This was not seen in cardiomyocytes. Multivariable regression analysis showed that increased phosphorus was an independent risk factor for both increased LV weight and cardiomyocyte size.
These data suggest left ventricular remodeling consists of cardiomyocyte hypertrophy and interstitial cell proliferation, but not cardiomyocyte proliferation. p27 and cyclin D2 may play important roles in the development of LVH. In addition, phosphorus can be an independent risk factor for the development of LVH.
American Journal of Nephrology 01/2010; 31(4):292-302. · 2.54 Impact Factor
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ABSTRACT: Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Vascular calcification is a common complication in CKD, and investigators have demonstrated that the extent and histoanatomic type of vascular calcification are predictors of subsequent vascular mortality. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification in patients with kidney disease, many questions remain unanswered. No longer can we accept the concept that vascular calcification in CKD is a passive process resulting from an elevated calcium-phosphate product. Rather, as a result of the metabolic insults of diabetes, dyslipidemia, oxidative stress, uremia, and hyperphosphatemia, "osteoblast-like" cells form in the vessel wall. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, osterix, and RUNX2 are crucial in the programming of osteogenesis. Thus, the simultaneous increase in arterial osteochondrocytic programs and reduction in active cellular defense mechanisms creates the "perfect storm" of vascular calcification seen in ESRD. Innovative clinical studies addressing the combined use of inhibitors that work on vascular calcification through distinct molecular mechanisms, such as fetuin-A, osteopontin, and bone morphogenic protein 7, among others, will be necessary to reduce significantly the accrual of vascular calcifications and cardiovascular mortality in kidney disease. In addition, the roles of oxidative stress and inflammation on the fate of smooth muscle vascular cells and their function deserve further translational investigation.
Journal of the American Society of Nephrology 06/2009; 20(7):1453-64. · 9.66 Impact Factor
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ABSTRACT: Glial cells missing-2 (Gcm2) is the key regulating transcription factor for parathyroid gland development. The continued expression of high levels of Gcm2 in mature parathyroid glands suggests that it is required for maintenance of parathyroid cell differentiation. The role of Gcm2 in parathyroid cell physiology, however, has not been fully studied. In this study, we examined the effects of Gcm2 silencing on cultured human parathyroid cells. Collagenase-dispersed human parathyroid cells from patients with chronic kidney disease were placed in monolayer cultures and infected with lentivirus expressing shRNA for human Gcm2. Seventy-two hours after infection, mRNA was processed and analyzed for Gcm2, PTH, vitamin D receptor (VDR), calcium-sensing receptor (CaR), 25-hydroxyvitamin D(3) 1-alpha-hydroxylase (1-OHase), and proliferating cell nuclear antigen (PCNA) by real-time PCR (qPCR). Protein expression of affected genes was analyzed by immunoblot 72 h after infection. Gcm2 mRNA and protein were decreased by 74.2 +/- 12.2% (SD; n = 3 experiments; p < 0.01) and 67.5 +/- 15.7% (n = 2; p < 0.01), respectively. CaR mRNA and protein were reduced by 47.8 +/- 21.1% (n = 3; p < 0.01) and 48.1 +/- 4.3% (n = 3; p < 0.01), respectively. However, VDR, PTH, 1-OHase, and PCNA were not significantly affected by Gcm2 silencing. Further analysis of CaR mRNA indicated that transcripts containing exon 1B, derived by transcription from CaR promoter 2, were downregulated (58.8 +/- 19.27%; n = 3; p < 0.05) by Gcm2 silencing. Exon 1A-containing transcripts from promoter 1 were expressed at very low levels in the cultures. These results indicate that one function of Gcm2 is to maintain high levels of CaR expression in parathyroid cells.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2009; 24(7):1173-9. · 6.04 Impact Factor
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ABSTRACT: Vascular calcium deposition in end-stage renal disease occurs commonly, but its relation to cardiovascular risk factors and fetuin-A levels in African Americans is not known. Compliant African American patients who were undergoing hemodialysis (HD; n = 17) agreed to undergo 64-slice multidetector computed tomography for the assessment of coronary artery calcium score (CACS). The relation between traditional cardiovascular risk factors (i.e., age; gender; dialysis vintage; history of diabetes; means of the previous 3 years of weekly predialysis blood pressure values and hemoglobin levels; means of monthly values of calcium, phosphorus, alkaline phosphatase, uric acid; and albumin; and means of quarterly measurements of parathyroid hormone and lipids) and fetuin-A levels and CACS was explored using univariate analyses. Serum phosphorus levels over the previous 3 years were well controlled. The CACS range was 0 to 3,877 Agatston units (mean 996, median 196). Among the tested variables, only fetuin-A was significantly and inversely associated with CACS (standardized beta = -0.64, 95% confidence interval -18.09 to -3.62, p = 0.006). There was no association between age and fetuin-A level (standardized beta = -0.02, 95% confidence interval -0.10 to 0.23). In conclusion, African-American patients who were undergoing long-term hemodialysis and with good phosphorus control exhibited a strong inverse correlation between fetuin-A level and CACS that was independent of age.
The American journal of cardiology 02/2009; 103(1):46-9. · 3.58 Impact Factor
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ABSTRACT: Hyperphosphatemia is associated with vascular calcification and increased cardiovascular morbidity and mortality. Angiotensin-converting enzyme inhibitors are beneficial in suppressing the progression of kidney and cardiovascular disease. The present studies explore the influence of enalapril and sevelamer carbonate on renal function, vascular calcification and mortality in long-term experimental uremia.
Normal and 5/6 nephrectomized rats were fed a high-phosphorus diet for 4 months and treated with enalapril or the combination of both enalapril and sevelamer carbonate.
The rats treated with enalapril alone or both enalapril and sevelamer had less deterioration in renal function compared to uremic control as seen by lower serum creatinine (1.6, 1.6 vs. 2.1 mg/dl, respectively, p < 0.05) and higher creatinine clearance. They also exhibited attenuated mortality (23.5, 12.5 vs. 75%, respectively, p < 0.01) and inhibition of myocardial hypertrophy. Enalapril alone did not suppress secondary hyperparathyroidism or vascular calcification. Combination therapy with both enalapril and sevelamer carbonate ameliorated secondary hyperparathyroidism and vascular calcification (calcium content: 854 +/- 40 vs. 1,735 +/- 479 microg/g wet tissue) compared to uremic controls.
In these experiments, animal mortality and myocardial hypertrophy were significantly reduced by both enalapril alone and enalapril in combination with sevelamer. In addition, sevelamer carbonate induced beneficial effects on renal dysfunction, secondary hyperparathyroidism and vascular calcification.
American Journal of Nephrology 01/2009; 29(6):582-91. · 2.54 Impact Factor
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ABSTRACT: This study investigated the protective effect of the angiotensin-converting enzyme inhibitor, enalapril, and the vitamin D analog, paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.
Rats were made uremic by 5/6 nephrectomy and treated for 4 months as follows: (1) uremic + vehicle (n = 11); (2) uremic + enalapril (30 mg/l in drinking water, n = 13); (3) uremic + paricalcitol (200 ng 3x week, n = 6); (4) uremic + enalapril + paricalcitol (n = 14), and (5) controls (n = 6).
Cardiac NADPH oxidase activity increased by 300% in uremic rats compared to normal controls. Treatment with enalapril, paricalcitol or the combination of the two protected uremic rats from cardiac oxidative stress by inhibiting enzyme activity. Cardiac malondialdehyde (MDA) levels were significantly increased in uremic rats compared to normal controls. Only the combination therapy inhibited the increase in MDA levels in uremic rats. Cardiac glutathione was significantly reduced in uremic rats compared to normal controls. Enalapril, paricalcitol or the two in combination all protected against this reduction in glutathione. Cardiac copper/zinc superoxide dismutase (CuZn-SOD) activity decreased whereas manganese (Mn-SOD) activity increased in uremic rats compared to controls. Both mono and combination therapies ameliorated the alterations in cardiac SOD activity seen in uremic rats.
Enalapril, paricalcitol and their combined therapy afford protection against cardiac oxidative stress in uremia.
American Journal of Nephrology 12/2008; 29(5):465-72. · 2.54 Impact Factor
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Maria Vittoria Arcidiacono,
Mario Cozzolino,
Noah Spiegel,
Masanori Tokumoto,
Jing Yang,
Yan Lu,
Tetsuhiko Sato,
Carlo Lomonte,
Carlo Basile, Eduardo Slatopolsky,
Adriana S Dusso
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ABSTRACT: In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-alpha induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-alpha and TGF-alpha self-induction, mutating the core AP2 site of the human TGF-alpha promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-alpha. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-alpha self-induction using erlotinib, a highly specific inhibitor of TGF-alpha/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-alpha and are required for TGF-alpha self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-alpha self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-alpha mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-alpha promoter determine the severity of the hyperplasia driven by parathyroid TGF-alpha self-upregulation in secondary hyperparathyroidism.
Journal of the American Society of Nephrology 07/2008; 19(10):1919-28. · 9.66 Impact Factor
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Maria Vittoria Arcidiacono,
Tetsuhiko Sato,
Daniel Alvarez-Hernandez,
Jing Yang,
Masanori Tokumoto,
Ignacio Gonzalez-Suarez,
Yan Lu,
Yoshihiro Tominaga,
Jorge Cannata-Andia, Eduardo Slatopolsky,
Adriana S Dusso
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ABSTRACT: Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
Journal of the American Society of Nephrology 03/2008; 19(2):310-20. · 9.66 Impact Factor
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ABSTRACT: Extracellular Ca reduces parathyroid hormone (PTH) levels through several mechanisms, but many details of the intracellular steps involved have been difficult to elucidate because of the lack of a suitable parathyroid cell model. The present studies utilized our Ca-responsive bovine parathyroid organoid culture system (pseudoglands) to examine PTH mRNA in intact parathyroid cells. Increasing medium calcium from 0.4 to 3.0 mM reduced PTH mRNA to 20-30% of basal by 16 h. Reducing medium Ca from 3.0 to 0.4 mM restored PTH mRNA levels over a 24-h period. PTH mRNA was also reduced by the calcimimetic R-568, confirming the role of the calcium-sensing receptor. PTH decay rates were determined by placing pseudoglands in either 0.4 or 3.0 mM Ca for 2 h and then blocking gene transcription. PTH mRNA remained stable for at least 24 h in pseudoglands incubated in 0.4 mM Ca, but fell gradually by 62% in the presence of 3.0 mM Ca. Blocking transcription prior to the addition of high-Ca medium dramatically blunted the Ca-induced degradation of PTH mRNA, indicating that acceleration of PTH mRNA decay by Ca requires gene transcription. Pharmacologic investigation of the signaling pathways involved indicated that the Ca-induced reduction of PTH mRNA did not involve MAP kinase, phospholipase D, or cyclic AMP. However, increasing cytosolic Ca with thapsigargin or the Ca ionophore A23187 decreased PTH mRNA levels. In summary, Ca-mediated destabilization of PTH mRNA requires gene transcription and involves increases in cytosolic Ca.
Journal of Molecular Endocrinology 02/2008; 40(1):13-21. · 3.48 Impact Factor
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ABSTRACT: Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.
Journal of the American Society of Nephrology 06/2007; 18(6):1796-806. · 9.66 Impact Factor
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ABSTRACT: Vitamin D analogs are being developed that retain therapeutic effects but are less calcemic and phosphatemic, a concern in CKD patients who are prone to vascular calcification. We tested a new analog of vitamin D, 2MbisP, and found that it suppresses PTH at doses that do not affect serum Ca or P.
Calcitriol is used for the treatment of secondary hyperparathyroidism. However, its use is often limited by the development of hypercalcemia and hyperphosphatemia, an important consideration in patients with chronic kidney disease (CKD) because they are prone to vascular calcification. To minimize this toxicity, structural modifications in the vitamin D molecule have led to the development of calcitriol analogs with selective actions.
In this study, we compared the effects of 1,25(OH)(2)D(3) and a new analog, 2-methylene-19-nor-(20S)-1 alpha-hydroxy-bishomopregnacalciferol (2MbisP), on the development of secondary hyperparathyroidism and established secondary hyperparathyroidism in uremic rats and on mobilization of calcium and phosphorus from bone in parathyroidectomized rats. The clearance from circulation, half-life, and binding affinities to the vitamin D-binding protein and vitamin D receptor of this compound were also evaluated.
Uremia produced a marked rise in plasma PTH, but treatment every other day for 2 wk with either 1,25(OH)(2)D(3) (4 ng) or 2MbisP (250, 750, 1500, or 3000 ng) suppressed this increase by >50%. The suppression by 1,25(OH)(2)D(3), however, was accompanied by increases in ionized calcium, phosphorus, and the calcium x phosphorus product, whereas these three parameters were unchanged by 2MbisP. The binding affinity of 2MbisP was 10-20 times less for the vitamin D receptor and 1000 times less for the serum vitamin D-binding protein compared with 1,25(OH)(2)D(3). Also, 2MbisP was cleared more rapidly from the circulation (t1/2 = 10 min) than 1,25-(OH)(2)D(3) (t1/2=7-9 h). In parathyroidectomized rats fed calcium-or phosphorus-deficient diets, daily injections of 2MbisP (1500 or 3000 ng), unlike 1,25(OH)(2)D(3) (50 ng), had no effect on calcium or phosphorus mobilization from bone.
In uremic rats, 2MbisP can suppress PTH at doses that do not affect plasma calcium, phosphorus, and calcium x phosphorus product. This new vitamin D analog may represent an important tool in the treatment of secondary hyperparathyroidism in patients with CKD.
Journal of Bone and Mineral Research 05/2007; 22(5):686-94. · 6.37 Impact Factor
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ABSTRACT: Secondary hyperparathyroidism commonly develops in patients with chronic kidney disease (CKD) in response to high phosphate, low calcium and low 1alpha,25-dihydroxyvitamin D(3) (calcitriol) levels. High levels of parathyroid hormone (PTH) accelerate bone turnover, with efflux of calcium and phosphate that can lead to vascular calcification. Treatment of secondary hyperparathyroidism with calcitriol and calcium-based phosphate binders can produce hypercalcemia and oversuppression of PTH, which results in adynamic bone that cannot buffer calcium and phosphate levels, and increased risk of vascular calcification. PTH levels must, therefore, be reduced to within a range that supports normal bone turnover and minimizes ectopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia (and have reduced calcemic activity) are a safer treatment for secondary hyperparathyroidism than calcitriol; these agents enhance the survival of patients with CKD. Several such analogs are now in use, and analogs with even greater selectivity than those currently used are in development. Parathyroid glands express both 25-hydroxylase and 1alpha-hydroxylase, which suggests that these enzymes might suppress parathyroid function by an autocrine mechanism. The risk of hypercalcemia with vitamin D analog therapy is reduced by the introduction of non-calcium-based phosphate binders and cinacalcet; furthermore, recent trials indicate that early intervention with vitamin D analogs in stage 3 and 4 CKD can correct PTH levels, and could prevent renal bone disease and prolong patient survival.
Nature Clinical Practice Endocrinology & Metabolism 03/2007; 3(2):134-44. · 7.55 Impact Factor
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Journal of Renal Nutrition 02/2007; 17(1):45-7. · 1.57 Impact Factor
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ABSTRACT: The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-alpha (TGF-alpha). TGF-alpha stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF-alpha and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF-alpha-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF-alpha exclusively or both TGF-alpha and EGFR to the rapid parathyroid growth induced by kidney disease and exacerbated by high-phosphorus (P) and low-calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (proliferating cell nuclear antigen/Ki67) induced by kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6 nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in TGF-alpha and EGFR content. Conversely, prevention of the increases in both TGF-alpha and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-alpha/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self-upregulation. Thus enhanced parathyroid TGF-alpha/EGFR expression, self-upregulation, and growth signals occur early in kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid hyperplasia.
American journal of physiology. Renal physiology 12/2005; 289(5):F1096-102. · 3.68 Impact Factor
