title: Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells: Implications for diabetic nephropathy.
abstract: Hypertrophy of human mesangial cells (HMC) is among the earliest characteristics in patients with diabetic nephropathy (DN). Recently, we observed the upregulation of parathyroid hormone (PTH)-related protein (PTHrP) in experimental DN, associated with renal hypertrophy. Herein, we first examined whether PTHrP was overexpressed in human DN, and next assessed the putative role of this protein on high glucose (HG)-induced HMC hypertrophy. As previously found in mice, kidneys from diabetic patients showed an increased tubular and glomerular immunostaining for PTHrP. In HMC, HG medium increased PTHrP protein expression associated with the development of hypertrophy as assessed by cell protein content. This effect was also induced by PTHrP(1-36). HG and PTHrP(1-36)-induced hypertrophy were associated with an increase in cyclin D1 and p27Kip1 protein expression, a decreased cyclin E expression, and the prevention of cyclin E/cdk2 complex activation. Both PTHrP neutralizing antiserum (α-PTHrP) and the PTH/PTHrP receptor antagonist (JB4250) were able to abolish HG induction of hypertrophy, the aforementioned changes in cell cycle proteins, and also TGF-β1 up-regulation. Moreover, the capability of both HG and PTHrP(1-36) to induce HMC hypertrophy was abolished by α-TGFβ1. These data show for the first time that PTHrP is upregulated in the kidney of patients with DN. Our findings also demonstrate that PTHrP acts as an important mediator of HG-induced HMC hypertrophy by modulating cell cycle regulatory proteins and TGF-β1.
authors: Laboratory of Renal Physiology and Experimental Nephrology, Department of Physiology, University of Alcalá, Alcalá de Herares, Spain.
authors: Arantxa
authors: A
authors: Ortega
authors: Montserrat
authors: M
authors: Romero
authors: Adriana
authors: A
authors: Izquierdo
authors: Nuria
authors: N
authors: Troyano
authors: Yolanda
authors: Y
authors: Arce
authors: Juan Antonio
authors: JA
authors: Ardura
authors: María Isabel
authors: MI
authors: Arenas
authors: Jordi
authors: J
authors: Bover
authors: Pedro
authors: P
authors: Esbrit
authors: Ricardo J
authors: RJ
authors: Bosch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D019927:Cyclin E; D044162:Parathyroid Hormone-Related Protein; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2