Parathyroid hormone-related protein induces hypertrophy in podocytes via TGF- 1 and p27Kip1: implications for diabetic nephropathy

Abstract

PTHrP seems to participate in the hypertrophic signalling triggered by HG. In this condition, AngII induces the upregulation of PTHrP, which might induce the expression of TGF-beta(1) and p27(Kip1). These findings provide new insights into the protective effects of AngII antagonists in DN, opening new paths for intervention.

Parathyroid Hormone-Related Protein as a Mediator of Renal Damage: New Evidence from Experimental as well as Human Nephropathies

“…Although the STZ model has limitations for assessing long-term histomorphological changes in the diabetic kidney (Gross et al, 2004); our findings might have pathophysiological implications since the amount of proteinuria is a reliable predictor of diabetic nephropathy (D'Amico & Bazzi, 2003;Hirschberg, 1996). In a more recent study, Romero et al (2010) observed that PTHrP plays a key role in the mechanisms of HG-induced podocyte hypertrophy. In these studies, HG-induced podocyte hypertrophy was inhibited by the presence of a specific PTHrP neutralizing antibody.…”

“…In this way, while PTHrP (1-36) was shown to stimulate cyclin D 1, thus promoting podocytes to enter into G 1 , it also downregulates cyclin E, hence blocking the cell cycle later in G 1 . Moreover, PTHrP is able to upregulate the negative cell cycle regulatory protein p27 Kip1 which plays a key role in diabetic cell hypertrophy by preventing activation of cyclin E activity and arresting the cell cycle later in G 1 (Huang & Preisig, 2000;Romero et al, 2010). Interestingly, Romero et al (2010) found that the pharmacological blockade of the PTH1R inhibited the p27 Kip1 upregulation induced by both HG and AngII.…”

“…Moreover, PTHrP is able to upregulate the negative cell cycle regulatory protein p27 Kip1 which plays a key role in diabetic cell hypertrophy by preventing activation of cyclin E activity and arresting the cell cycle later in G 1 (Huang & Preisig, 2000;Romero et al, 2010). Interestingly, Romero et al (2010) found that the pharmacological blockade of the PTH1R inhibited the p27 Kip1 upregulation induced by both HG and AngII. Taken together, these data suggest that PTHrP might mediate the hypertrophic signalling acting in an autocrine/intracrine fashion through the PTH1R receptor.…”

“…Taken together, these data suggest that PTHrP might mediate the hypertrophic signalling acting in an autocrine/intracrine fashion through the PTH1R receptor. To discern the mechanism involved in the stimulation of p27 kip1 induced by both PTHrP and TGF-β 1, Romero et al (2010) performed two experimental approaches. First, they found that using a PTHrP siRNA inhibited the ability of HG and AngII to stimulate the upregulation of p27 Kip1 , albeit it could not prevent the TGF-β 1 upregulation of this protein.…”

“…During the last years, studies to define the physiopathological role of PTHrP in the renal context have been carried out, using experimental models of tubulointerstitial or glomerular damage. In both entities the direct implication of PTHrP has been demonstrated, showing the important role of this protein in the mechanisms that regulate the cell cycle, inflammation and fibrosis, which indicates the possibility of new pathways of therapeutic intervention Rámila et al, 2008;Romero et al, 2010). The following paragraphs describe the emerging role of the PTHrP system in acute and chronic renal injury, product of intense investigation for over a decade.…”