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Transforming growth factor-beta modulates the parathyroid hormone-related protein-induced responses in renal
F Law1, R Rizzoli, J P Bonjour
1Department of Medicine, University Hospital, Geneva, Switzerland.
Abstract:
PTH-related protein (PTHrP), the major mediator of hypercalcemia of malignancy, reduces tubular phosphate (Pi) reabsorption through its PTH-like renotropic actions. Another peptide detected in tumoral cells, transforming growth factor-beta (TGF beta), has been shown to considerably suppress the sodium-dependent Pi transport system present in the apical membrane of renal epithelial cells. The unexplored interactions between TGF beta and PTHrP were examined in opossum kidney (OK) cells. Using confluent OK cells, we showed that TGF beta attenuated the inhibition of Pi transport mediated by PTHrP. Similarly, 18 h TGF beta incubation resulted in a substantial reduction of the cAMP response elicited by PTHrP without apparent involvement of pertussis toxin-sensitive guanine nucleotide binding protein(s). The number of PTHrP(1-34) binding sites in TGF beta-treated cells was decreased with the affinity unchanged. Forskolin- and prostaglandin E2-stimulated cAMP productions were not significantly altered by TGF beta treatment. Therefore, TGF beta reduced Pi transport in OK cells, modulated the actions of PTHrP, and decreased its receptor number. Whether this happens in vivo is as yet unknown.
Insights
Transforming growth factor-beta (TGF beta) modulates the effects of PTH-related protein (PTHrP) on kidney phosphate transport. TGF beta reduces PTHrP
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- PTH-related protein (PTHrP) causes hypercalcemia by reducing kidney phosphate reabsorption.
- Tumoral transforming growth factor-beta (TGF beta) suppresses renal epithelial phosphate transport.
Purpose of the Study:
- To investigate the interaction between TGF beta and PTHrP in renal phosphate handling.
- To elucidate the cellular mechanisms underlying TGF beta's modulation of PTHrP action.
Main Methods:
- Experiments were conducted using opossum kidney (OK) cells.
- Phosphate transport, cAMP signaling, and PTHrP binding were assessed after TGF beta treatment.
Main Results:
- TGF beta attenuated PTHrP-induced inhibition of phosphate transport.
- TGF beta reduced the cAMP response to PTHrP and decreased PTHrP receptor number.
- TGF beta did not affect forskolin- or prostaglandin E2-stimulated cAMP production.
Conclusions:
- TGF beta suppresses renal phosphate transport in OK cells.
- TGF beta modulates PTHrP action by reducing its receptor availability.
- The in vivo relevance of these findings remains to be determined.