The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes

被引:31
作者
Izquierdo, A.
Lopez-Luna, P.
Ortega, A.
Romero, M.
Gutierrez-Tarres, M. A.
Arribas, I.
Alvarez, M. J. R.
Esbrit, P.
Bosch, R. J.
机构
[1] Univ Alcala de Henares, Fac Med, Dept Fisiol, Lab Renal Physiol & Expt Nephrol, Alcala De Henares 28871, Spain
[2] Fdn Jimenez Diaz, Bone & Mineral Metab Lab, E-28040 Madrid, Spain
[3] Hosp Principe Asturias, Dept Biochem, Alcala De Henares, Spain
关键词
diabetic nephropathy; diabetes mellitus; parathyroid hormone-related protein; PTH1; receptor; proteinuria;
D O I
10.1038/sj.ki.5000195
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
The pathophysiology of the diabetic kidney (e. g., hypertrophy, increased urinary albumin excretion (UAE)) is still ill-defined. Parathyroid hormone-related protein (PTHrP) is overexpressed in several nephropathies, but its role remains unclear. We evaluated the effect of high glucose on PTHrP and the PTH1 receptor (PTH1R) protein (by Western blot and immunohistochemistry) in the kidney of mice with streptozotocin-induced diabetes, and in several mouse renal cells in vitro. Diabetic mice showed a significantly increased renal expression of PTHrP and PTH1R proteins within 2-8 weeks from the onset of diabetes. These animals exhibited an intense immunostaining for both proteins in the renal tubules and glomeruli. Using transgenic mice overexpressing PTHrP targeted to the renal proximal tubule, we found a significant increase in the renal hypertrophy index and in UAE in these diabetic mice relative to their control littermates. Moreover, logistic regression analysis showed a significant association between both PTHrP and PTH1R protein levels and UAE in all diabetic mice throughout the study. High-glucose (25mM) medium was found to increase PTHrP and PTH1R in tubuloepithelial cells, mesangial cells, and podocytes in vitro. Moreover, this increase in PTHrP (but not that of PTH1R) was inhibited by the AT1 receptor antagonist losartan. Collectively, these results indicate that the renal PTHrP/PTH1R system is upregulated in streptozotozin- induced diabetes in mice, and appears to adversely affect the outcome of diabetic renal disease. Our findings also suggest that angiotensin II might have a role in the PTHrP upregulation in this condition.
引用
收藏
页码:2171 / 2178
页数:8
相关论文
共 60 条
[1]   Immunohistochemical detection of parathyroid hormone-related protein in a rare variant of hepatic neoplasm (sclerosing hepatic carcinoma) [J].
Albar, JP ;
DeMiguel, F ;
Esbrit, P ;
Miranda, R ;
FernandezFlores, A ;
Sarasa, JL .
HUMAN PATHOLOGY, 1996, 27 (07) :728-731
[2]  
Alvarez J, 2002, DEVELOPMENT, V129, P1913
[3]   Effects of transforming growth factor β1 on cell growth and parathyroid hormone-related protein in Walker 256 tumor cells [J].
Benitez-Verguizas, J ;
Loarte, D ;
de Miguel, F ;
Esbrit, P .
LIFE SCIENCES, 1999, 65 (17) :1807-1816
[4]   Effects of parathyroid hormone-related protein on human mesangial cells in culture [J].
Bosch, RJ ;
Rojo-Linares, P ;
Torrecillas-Casamayor, G ;
Iglesias-Cruz, M ;
Rodríguez-Puyol, D ;
Rodríguez-Puyol, M .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1999, 277 (06) :E990-E995
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]   Angiotensin II and its receptors in the diabetic kidney [J].
Burns, KD .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2000, 36 (03) :449-467
[7]  
BURTIS WJ, 1987, J BIOL CHEM, V262, P7151
[8]   Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria - Relation to glomerular hyperfiltration [J].
Chiarelli, F ;
Cipollone, F ;
Romano, F ;
Tumini, S ;
Costantini, F ;
di Ricco, L ;
Pomilio, M ;
Pierdomenico, SD ;
Marini, M ;
Cuccurullo, F ;
Mezzetti, A .
DIABETES, 2000, 49 (07) :1258-1263
[9]  
Choi KC, 1997, KIDNEY INT, pS23
[10]   Parathyroid hormone-related protein and its receptors:: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets [J].
Clemens, TL ;
Cormier, S ;
Eichinger, A ;
Endlich, K ;
Fiaschi-Taesch, N ;
Fischer, E ;
Friedman, PA ;
Karaplis, AC ;
Massfelder, T ;
Rossert, J ;
Schlüter, KD ;
Silve, C ;
Stewart, AF ;
Takane, K ;
Helwig, JJ .
BRITISH JOURNAL OF PHARMACOLOGY, 2001, 134 (06) :1113-1136