TY - JOUR
T1 - p21WAF1 and transforming growth factor-α mediate dietary phosphate regulation of parathyroid cell growth
AU - Dusso, Adriana S.
AU - Pavlopoulos, Tricia
AU - Naumovich, Lech
AU - Lu, Yan
AU - Finch, Jane
AU - Brown, Alex J.
AU - Morrissey, Jeremiah
AU - Slatopolsky, Eduardo
N1 - Funding Information:
This work was supported in part by National Institute of Diabetes and Digestive and Kidney diseases grants DK-09976, DK-30178, DK-07126, and DK53774, and by GelTex Pharmaceuticals, Inc. (Waltham, MA, USA). The authors wish to express their appreciation to Dr. Christine Sorenson (Department of Biochemistry) for valuable suggestions for the experimental approach; Dr. Maria Isabel Colombo and Courtney Gelvermann (Department of Cell Biology and Physiology) for their assistance in the initial settings of Western blots for rat PT-p21; Cindy Ritter (Renal Division) for her assistance in immunohistochemical quantitation; and Dr. Gustavo Blanco (Department of Cell Biology and Physiology) and Marcos Vidal, M.S. (Renal Division) for their help in the densitometric analysis and graphs of Western blots and immunohistochemistry.
PY - 2001
Y1 - 2001
N2 - Background. The parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21WAF1 (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-α (TGF-α), known to be elevated in hyperplastic and adenomatous human PT glands. Methods. The time course for dietary P regulation of PT expression of TGF-α and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperparathyroidism. Results. In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT-TGF-α protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclear antigen (PCNA), an index of cell mitoses, correlated inversely with p21 and directly with TGF-α. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-α by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-α protein content. Conclusions. These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-α may function as an autocrine signal to stimulate growth further.
AB - Background. The parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21WAF1 (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-α (TGF-α), known to be elevated in hyperplastic and adenomatous human PT glands. Methods. The time course for dietary P regulation of PT expression of TGF-α and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperparathyroidism. Results. In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT-TGF-α protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclear antigen (PCNA), an index of cell mitoses, correlated inversely with p21 and directly with TGF-α. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-α by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-α protein content. Conclusions. These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-α may function as an autocrine signal to stimulate growth further.
KW - Growth arrest
KW - Hyperparathyroidism
KW - Hyperplasia
KW - Renal failure
KW - Uremia
KW - p21
UR - http://www.scopus.com/inward/record.url?scp=0035094077&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.2001.059003855.x
DO - 10.1046/j.1523-1755.2001.059003855.x
M3 - Article
C2 - 11231340
AN - SCOPUS:0035094077
SN - 0085-2538
VL - 59
SP - 855
EP - 865
JO - Kidney International
JF - Kidney International
IS - 3
ER -