Abstract
Little is known about the cross-talk between parathyroid hormone (PTH) related protein (PTHrP) and TGF-β1 in mesangial cells (MCs). Our results showed that PTHrP treatment (≤3 h) induced internalization of PTH1R (PTH/PTHrP receptor)–TβRII (TGF-β type 2 receptor) complex and suppressed TGF-β1-mediated Smad2/3 activation and fibronectin (FN) up-regulation. However, prolonged PTHrP treatment (12–48 h) failed to induce PTH1R–TβRII association and internalization. Total protein levels of PTH1R and TβRII were unaffected by PTHrP treatment. These results suggest that internalization of PTH1R and TβRII after short PTHrP treatment might not lead to their proteolytic destruction, allowing the receptors to be recycled back to the plasma membrane during prolonged PTHrP exposure. Receptor re-expression at the cell surface allows PTHrP to switch from its initial inhibitory effect to promote induction of FN. Our study thus demonstrates the dual roles of PTHrP on TGF-β1 signaling and FN up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for diabetic kidney disease (DKD).
Highlights
Parathyroid hormone (PTH) related protein (PTHrP) is a widespread factor in fetal and adult tissues and plays a key role in the development and differentiation by paracrine/autocrine/intracrine pathways [1,2,3]
Since short PTH treatment inhibits TGF-β1 signaling in Mesangial cell (MC) [26], it suggests that PTH related protein (PTHrP) might attenuate the sensitivity of MCs to TGF-β1 in the short term
Our results showed that short PTHrP treatment induced the internalization of PTH/PTHrP receptor (PTH1R)–TGF-β type receptor (TβRII) complex, decreased cell surface TβRII, and inhibited TGF-β-mediated Smad2/3 activation and FN up-regulation in rat MCs, whereas prolonged PTHrP incubation could not suppress TGF-β/Smad signaling, but rather induced FN up-regulation
Summary
Parathyroid hormone (PTH) related protein (PTHrP) is a widespread factor in fetal and adult tissues and plays a key role in the development and differentiation by paracrine/autocrine/intracrine pathways [1,2,3]. PTH1R is highly expressed in bone and kidney and mediates the PTH-dependent regulation of mineral ion homeostasis [7,8,9]. PTHrP is widely expressed in the kidney and exerts a modulatory action on renal function [10,11]. PTHrP is known to be up-regulated in several experimental nephropathies such as acute renal injury, diabetic kidney disease (DKD), and obstructive nephropathy [12,13,14], but the downstream pathophysiologic effects are still poorly understood
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