Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2.
Runx2 is a key transcription factor in bone development regulating several processes, including osteoblast apoptosis. The antiapoptotic effects of parathyroid hormone (PTH) in osteoblasts depend on Runx2-mediated transcription of prosurvival genes. In the kidney, PTH-related protein (PTHrP) promotes tubulointerstitial cell survival by activating the PTH/PTHrP type 1 receptor. We found that Runx2 is expressed in renal tubuloepithelial MCT and HK2 cell lines in vitro and in the mouse kidney tubuloepithelium in vivo. The 1-36 amino-acid fragment of PTHrP was found to increase the expression and nuclear translocation of Runx2 in both cell lines in a dose- and time-dependent manner. PTHrP(1-36) protected renal tubuloepithelial cells from folic acid toxicity and serum deprivation, an effect inhibited by a dominant-negative Runx2 construct or a Runx2 siRNA. Furthermore, PTHrP(1-36) upregulated the antiapoptotic proteins Bcl-2 and osteopontin, and these effects were abolished by Runx2 siRNA. Runx2, osteopontin, and Bcl-2 were increased in tubuloepithelial cells from transgenic mice with PTHrP overexpression and in wild-type mice with acute or chronic renal failure. Thus, PTHrP regulates renal tubuloepithelial cell survival via Runx2 in the mammalian kidney.
Bone and Mineral Metabolism Laboratory, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, and Instituto de Salud Carlos III-RETICEF RD06/0013/1002, Madrid, Spain. jaardura@fjd.es
Juan A
JA
Ardura
Ana B
AB
Sanz
Alberto
A
Ortiz
Pedro
P
Esbrit
D021581:Active Transport, Cell Nucleus; D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005492:Folic Acid / Q000633:toxicity; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D053495:Osteopontin / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D050659:Core Binding Factor Alpha 1 Subunit; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; C079957:parathyroid hormone-related peptide (1-36); D053495:Osteopontin; D005492:Folic Acid