p21WAF1 and TGF-α mediate parathyroid growth arrest by vitamin D and high calcium

Cozzolino, Mario; Lü, Yan; Finch, Jane; Slatopolsky, Eduardo; Dusso, Adriana

doi:10.1046/j.1523-1755.2001.00042.x

Cited by 162 publications

(129 citation statements)

References 30 publications

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“…Reductions in parathyroid LAP1, known to suppress cyclin D1 directly, 24 could further aggravate the hyperplastic growth driven by increased LIP. These findings and calcitriol efficacy in suppressing parathyroid 23 and A431 cell growth 38 suggest novel calcitriol antiproliferative properties. Calcitriol could either downregulate TGF-␣/EGFR induction of LIP synthesis or prevent LIP-induced decreases in cellular LAP/LIP ratio through induction of LAP, as demonstrated in osteoblasts, 22,39 renal cells, 22 and monocyte-macrophages, 40,41 the last through a VDR-mediated mechanism.…”

Section: Discussionmentioning

confidence: 78%

“…Table 1 shows that PTG enlargement from week 2 to week 4 after five-sixths NX and 0.9% dietary phosphorus (P) intake were associated with a 25% reduction in VDR, sufficient to cause resistance to 1,25D suppression of serum PTH. A 4-ng dosage of 1,25D, which effectively normalized serum PTH when administered every other day during the first week after five-sixths NX, 23 was no longer effective by week 4 (control 237.6 Ϯ 59.5 pg/ml [n ϭ 10]; 1,25D w4 163.7 Ϯ 75.8 [n ϭ 9]). Furthermore, whereas PTG enlargement from week 2 to week 4 correlated directly with enhanced parathyroid TGF-␣ (r ϭ 0.64, P Ͻ 0.02; n ϭ 12), EGFR content remained unchanged.…”

Section: Resultsmentioning

confidence: 99%

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EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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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-␣ 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-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/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-␤, 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-␤ 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-␣ 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.

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Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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“…Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and transforming growth factor-␣ (TGF-␣) was performed on sections of 10% neutral buffered formalin-fixed overnight at 4°C and switched to 70% ethanol, paraffin embedded parathyroid glands following protocols described in previous studies (21). Specificity of the primary antibodies was tested by immunohistochemical staining of rat parathyroid tissue replacing the primary antibody with mouse IgG1.…”

Section: Immunohistochemical Analyses Of Parathyroid Glandsmentioning

confidence: 99%

“…Images of stained tissue sections were acquired using a DAGE-330 color camera and captured with a Pentium P-166 IBM compatible computer. The digitized images were converted to a gray scale and analyzed using Image-Pro plus software (Media Cybernetics) according to Mize's study (22) as described before (21). To eliminate variation, the microscope light source intensity used during image capture was kept constant for all sections stained on a given day.…”

Section: Immunohistochemical Analyses Of Parathyroid Glandsmentioning

confidence: 99%

The Effects of Sevelamer Hydrochloride and Calcium Carbonate on Kidney Calcification in Uremic Rats

Cozzolino

Dusso²,

Liapis

et al. 2002

Journal of the American Society of Nephrology

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101

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Abstract. The control of serum phosphorus (P) and calciumphosphate (Ca ϫ P) product is critical to the prevention of ectopic calcification in chronic renal failure (CRF). Whereas calcium (Ca) salts, the most commonly used phosphate binders, markedly increase serum Ca and positive Ca balance, the new calcium-and aluminum-free phosphate binder, sevelamer hydrochloride (RenaGel), reduces serum P without altering serum Ca in hemodialysis patients. Using an experimental model of CRF, these studies compare sevelamer and calcium carbonate (CaCO 3 ) in the control of serum P, secondary hyperparathyroidism (SH), and ectopic calcifications. 5/6 nephrectomized rats underwent one of the following treatments for 3 mo: uremic ϩ high-P diet (U-HP); UHP ϩ 3% CaCO 3 (U-HPϩC); UHP ϩ 3% sevelamer (U-HPϩS). Sevelamer treatment controlled serum P independent of increases in serum Ca, thus reducing serum Ca ϫ P product and further deterioration of renal function, as indicated by the highest creatinine clearances. Sevelamer was as effective as CaCO 3 in the control of high-P-induced SH, as shown by similar serum PTH levels, parathyroid (PT) gland weight, and markers of PT hyperplasia.Also, both P binders elicited similar efficacy in reducing the myocardial and hepatic calcifications induced by uremia. However, sevelamer caused a dramatic reduction of renal Ca deposition (29.8 Ϯ 8.6 g/g wet tissue) compared with both U-HP (175.5 Ϯ 45.7 g/g wet tissue, P Ͻ 0.01) and the U-HPϩC (58.9 Ϯ 13.7 g/g wet tissue, P Ͻ 0.04). Histochemical analyses using Von Kossa and Alizarin red S staining of kidney sections confirmed these findings. The high number of foci of calcification in the kidney of uremic controls (108 Ϯ 25) was reduced to 33.0 Ϯ 11.3 by CaCO 3 and decreased even further with sevelamer (16.4 Ϯ 8.9, P Ͻ 0.02 versus CaCO 3 ). Importantly, the degree of tubulointerstitial fibrosis was also markedly lower in U-HPϩS (5%) compared with either U-HPϩC (30%) or U-HP (50%). It is concluded that in experimental CRF in rats, despite a similar control of serum P and SH, sevelamer is more effective than CaCO 3 in preventing renal Ca deposition and tubulointerstitial fibrosis, including better preservation of renal function. These findings cannot be extrapolated to human disease, and further studies in patients are necessary to determine the benefits of either P binder.In end-stage renal disease, hyperphosphatemia and elevated calcium-phosphate (Ca ϫ P) product associate with ectopic calcifications and increased risk of calciphylaxis, resulting in higher prevalence of morbidity and mortality from cardiovascular events (1-6). High serum phosphorus (P) levels worsen uremia-induced secondary hyperparathyroidism by enhancing parathyroid hyperplasia and parathyroid hormone (PTH) synthesis and secretion (7-8). Elevated PTH levels cause ectopic calcification not only by enhancing serum P and Ca ϫ P product through inducing high bone turnover, but also by increasing both serum and intracellular calcium (Ca) (9 -10). The control of serum P in patients with ch...

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“…Dietary phosphate restriction can significantly lower FGF-23 levels [53][54][55] and could be more effective if started before serum phosphate levels increase. Vitamin D receptor agonists may effectively inhibit both the TGF-␣-converting enzyme/TGF␣/EGF receptor pathway and the RAAS in the parathyroid and kidney 90,91 and reduce vascular calcification, podocyte damage, 63,[92][93][94] and proteinuria through blockade of Wnt/␤-catenin signaling. 95 Vitamin D receptor agonists also may upregulate klotho 96 and exert an antiinflammatory action through the reduction of nuclear factor B.…”

Section: Insights From Recent Experimental Studies and Novel Therapeumentioning

confidence: 99%

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

Cozzolino

Gentile

Mazzaferro

et al. 2013

American Journal of Kidney Diseases

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Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. Am J Kidney Dis. xx(x):xxx. © 2013 by the National Kidney Foundation, Inc. INDEX WORDS:Chronic kidney disease; vitamin D deficiency; blood pressure; proteinuria; phosphate.C hronic kidney disease (CKD) is a silent killer.Four of 5 people with advanced CKD are not aware of the disease until death is imminent and kidney replacement therapy (dialysis or kidney transplantation) is unavoidable. Unfortunately, Ͻ10% of people requiring replacement therapy have access to it, and more than 1 million people worldwide die of untreated kidney failure each year because dialysis or kidney transplantation is unaffordable in most countries. This represents a huge economic burden, with global costs from 2000-2010 surpassing $1 trillion. 1,2 Worsening kidney function is associated with a marked increase in cardiovascular morbidity and mortality 1,3 independent of other risk factors. Coexistent hypertension is present in ϳ80% of patients with CKD and worsens cardiovascular outcomes because only 64% of patients with CKD achieve adequate blood pressure control. 4 As a consequence, only a minority of the hundreds of thousands of patients with stages 3 and 4 CKD reach kidney failure. 5 Proteinuria also is an important prognostic factor in patients with CKD. Although patients with nonproteinuric CKD are at greater risk of cardiovascular mortality than progression to kidney failure, the opposite may be true for the presence of proteinuria. Patients from the REIN (Ramipril Efficacy in Nephropathy) Study who were in the highest tertile of baseline proteinuria (protein excretion Ն3.8 g/d) also experienced the highest rate of glomerular filtration rate (GFR) loss during followup. 6 In addition, although post hoc analysis of RENAAL (Reduction of Endpoints in NIDDM [Non-InsulinDependent Diabetes Mellitus] With the Angiotensin II Antagonist Losartan) showed that 85% of patients with proteinuria with protein excretion Ն3 g/d reached the composite end point of doubling of serum creatinine level or end-stage renal disease (ESRD), only 44% of these patients reached the composite cardiovascular outcome. 7 Besides the we...

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p21WAF1 and TGF-α mediate parathyroid growth arrest by vitamin D and high calcium

Abstract: In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-alpha.

Cited by 162 publications

References 30 publications

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

The Effects of Sevelamer Hydrochloride and Calcium Carbonate on Kidney Calcification in Uremic Rats

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

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