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. 1. Diabetic Nephropathy (DN) End-stage renal failure due to diabetes mellitus, especially type 2 diabetes, has been recently described as a medical catastrophe of worldwide dimensions [1]. Diabetic nephropathy (DN) is characterized by the development of proteinuria and subsequent glomerulosclerosis, conditions which are always preceded by renal cell hypertrophy [2]. Although the diabetic kidney is extremely variable, from near normal size to even small fibrotic kidney, renal enlargement due to cellular hypertrophy and hyperplasia is an early feature of the disease both in human and in experimental animal models, especially in the absence of insulin treatment. Hypertrophy of tubuloepithelial as well as glomerular cells, including both visceral epithelial (podocytes) and mesangial cells, is an early hallmark of diabetes renal involvement [3–5]. Over time, glomerular cell hypertrophy might become a maladaptive response leading to glomerulosclerosis. Although the mechanisms by which high glucose (HG) leads to renal cell hypertrophy are still not completely understood, they appear to involve cell entry into the cell cycle—associated with cyclin D1 kinase activation early in G1—and subsequent arrest at the G1/S interphase, implicating inhibition or insufficient activation of cyclin E kinase, to permit
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