A transgenic mouse model for studying the role of the parathyroid hormone-related protein system in renal injury

Abstract

Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches.

Figure 1

Schematic representation of the different transgenes used to generate the PTHrP-overexperssing mice. Construct A, containing sequences for the γ-glutamyl transpeptidase-I (GGT-I) promoter, cDNA sequences for the Tet transactivator protein (tTA), and the SV-40 T antigen 3′ UTR, was used to generate GGT-tTA transgenic mice, resulting in specific expression of the tTA protein in the renal proximal tubule cells. Construct B, containing sequences for a hybrid regulatory element composed of a heptamerized tetracycline operator (TetoX7) fused to a minimal human cytomegalovirus promoter element, the human growth hormone (hGH) 3′ UTR, and hPTHrP (1–141) cDNA sequences, was used to generate Teto-PTHrP transgenic mice. Hemizygote mice bearing the construct A were bred with construct B-bearing hemizygote mice to induce PTHrP overexpression in renal proximal tubule cells.

Figure 2

Schematic representation of the different actions whereby PTHrP might promote inflammation and fibrogenesis in the injured kidney.