Expression of parathyroid hormone-related protein in the rat glomerulus and tubule during recovery from renal ischemia.

Abstract

Parathyroid hormone-related protein (PTHrP) is widely expressed in normal adult and fetal tissues, where it acts in an autocrine/paracrine fashion, stimulates growth and differentiation, and shares early response gene characteristics. Since recovery from renal injury is associated with release of local growth factors, we examined the expression and localization of PTHrP in normal and ischemic adult rat kidney. Male SpragueDawley rats underwent complete bilateral renal artery occlusion for 45 min, followed by reperfusion for 15 min., and 2,6, 24, 48, and 72 h. Renal PTHrP mRNA levels, when compared with sham-operated animals, increased twofold after ischemia, and peaked within 6 h after reperfusion. PTH receptor, j-actin, and cyclophilin mRNA levels all decreased after ischemia. PTHrP immunohistochemical staining intensity increased in proximal tubular cells after ischemia, changing its location from diffusely cytoplasmic to subapical by 24 h after reperfusion. In addition, PTHrP localized to glomerular epithelial cells (visceral and parietal), but not to mesangial cells. PTHrP and PTH stimulated proliferation two-to threefold in cultured mesangial cells. We conclude that PTHrP mRNA and protein production are upregulated after acute renal ischemic injury, that PTHrP is present in glomerulus and in both proximal and distal tubular cells, and that PTHrP stimulates DNA synthesis in mesangial cells. The precise functions of PTHrP in normal and injured kidney remain to be defined. (J. Clin. Invest. 1993.

Role of Parathyroid Hormone–Related Protein in Tubulointerstitial Apoptosis and Fibrosis after Folic Acid–Induced Nephrotoxicity

“…PTHrP has growth-regulatory features in tubuloepithelial cells (11,12,17,35), but current evidence does not support that it has a significant role in the renal regenerative process after acute kidney injury: (1) The PTH1R gene is downregulated rapidly, and targeted delivery of PTHrP to the proximal tubule does not provide protection in this setting (13,17,39); and (2) renal PTHrP upregulation but not tubular hyperplasia in the FA-injured kidney can be prevented by Ang II blockers (21). However, PTHrP seems to be involved in the mechanisms that are associated with Ang II-induced renal injury (16,21).…”

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

“…Subsequently, sections were immunostained with an affinity purified goat anti-human HGF polyclonal antibody (Santa Cruz) at a 1:50 dilution. Visualization of the staining was achieved using the species-appropriate avidin-biotin complex system as described previously (39).…”

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

“…Pioneer studies by Soifer et al (1993) at the beginning of the 90´s suggested the implication of PTHrP in the mechanisms of injury and/or repair of the tubular epithelium after ischemic ARI. From then on, the majority of investigations have studied experimental nephropathies characterized by tubular affectation (Fiaschi-Taesch et al, 2004;Largo et al, 1999;Lorenzo et al, 2002;Ortega et al, 2005;Santos et al, 2001).…”

“…Several growth factors and cytokines, acting in an autocrine and paracrine manner, appear to participate in the repair process of the tubular epithelium in this setting (Fiaschi-Taesch et al, 2004;Gobe et al, 2000;Humes et al, 1995;Matsumoto & Nakamura, 2001;Vukicevic et al, 1998). The mitogenic features of PTHrP and its early overexpression after renal injury in experimental models of acute renal failure (ARF), induced by either ischemia or nephrotoxins, initially suggested that PTHrP could participate in the regenerative process after ARI (Santos et al, 2001;Soifer et al, 1993). However, this putative role of PTHrP in the acutely damaged kidney was intriguing, since the PTH1R gene was found to be rapidly downregulated following ARI (Santos et al, 2001;Soifer et al, 1993).…”

“…The mitogenic features of PTHrP and its early overexpression after renal injury in experimental models of acute renal failure (ARF), induced by either ischemia or nephrotoxins, initially suggested that PTHrP could participate in the regenerative process after ARI (Santos et al, 2001;Soifer et al, 1993). However, this putative role of PTHrP in the acutely damaged kidney was intriguing, since the PTH1R gene was found to be rapidly downregulated following ARI (Santos et al, 2001;Soifer et al, 1993). This is in sharp contrast to other well characterized renal mitogens, such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), whose receptors are upregulated after ARI (Humes et al, 1995;Matsumoto & Nakamura, 2001).…”