Novel role of parathyroid hormone-related protein in the pathophysiology of the diabetic kidney: Evidence from experimental and human diabetic nephropathy

Parathyroid hormone-related protein (PTHrP) and its receptor type 1 (PTH1R) are extensively expressed in the kidney, where they are able to modulate renal function. Renal PTHrP is known to be overexpressed in acute renal injury. Recently, we hypothesized that PTHrP involvement in the mechanisms of renal injury might not be limited to conditions with predominant damage of the renal tubulointerstitium and might be extended to glomerular diseases, such as diabetic nephropathy (DN). In experimental DN, the overexpression of both PTHrP and the PTH1R contributes to the development of renal hypertrophy as well as proteinuria. More recent data have shown, for the first time, that PTHrP is upregulated in the kidney from patients with DN. Collectively, animal and human studies have shown that PTHrP acts as an important mediator of diabetic renal cell hypertrophy by a mechanism which involves the modulation of cell cycle regulatory proteins and TGF-β1. Furthermore, angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be responsible for PTHrP upregulation in these conditions. 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.N. Olea is the recipient of a Research Contract from the Comunidad Autónoma de Madrid (S-BIO-2083-2006) and the University of Alcalá. A. Izquierdo is currently Assistant Professor at the Rey Juan Carlos University, Alcorc´on, Madrid. This work was supported in part by Grants from Ministerio de Educaci´on y Cultura of Spain (SAF2002- 04356-C03-01, -02, and -03) Ministerio de Ciencia e Innovación (SAF2009-12009-C02-01), Instituto de Salud Carlos III (RETICEF RD06/0013/1002 and RD12/0043/0008 and PI12/02825), the Spanish Society of Nephrology, and the Eugenio Rodr´ıguez Pascual Foundation