The site of synthesis of FGF23 is primarily the bone tissue, more specifically osteocytes and osteoblasts, although FGF23 is also espressed by brain, thymus, liver, spleen and heart. Since the kidney is an important target of FGF23, and the circulating levels of FGF23 have been found to increase in association with disease progression and cardiovascular events in chronic kidney disease and diabetic nephropathy, we wondered whether the kidney could be a source of FGF23 during the development of renal disease. Few data are so far available showing that renal tissue expressed FGF23 at very low level, if any, in normal conditions and in uremic rats. We took advantage of the Zucker diabetic fatty rat model of human type 2 diabetic nephropathy characterized by obesity, hyperlipidemia, insulin resistance, progressive renal injury and cardiac abnormalities and evaluated the expression of FGF23 in the kidney during the course of the disease. We also investigated whether renoprotective effects of ACE inhibitor in this model were associated with modulation of renal FGF23 and Klotho expression. The present study shows that the kidney of ZDF rats, a model resembling human type 2 diabetic nephropathy, expressed FGF23 starting from the age of months when rats have already significant levels of proteinuria and signs of renal injury. FGF23 mRNA expression further increased with time as diabetic disease progressed, reaching levels that were times higher than at months. To our knowledge this is the first evidence of FGF23 production by the kidney during renal disease progression. Upregulation of FGF23 mRNA resulted in the expression of the alpha-Asarone biological activity corresponding protein BI-78D3 localized at proximal and distal tubules in focal areas of the kidney. A previous study by Mirams et al that analyzed FGF23 mRNA expression in several human tissues showed that FGF23 was detectable in kidney tissue at low levels. Actually, the highest expression was found in bone followed by kidney medulla, liver, thyroid and kidney cortex. FGF23 bone expression was approximately 30 times higher than renal expression in normal conditions, but no data are available that compared tissues from patients with renal disease. The prevailing paradigm proposes the bone as the main tissue that senses changes in phosphate balance and produces FGF23. The present data would add the kidney as a direct sensor organ that may interfere in phosphate homeostasis via its own FGF23 production. It is noteworthy that the FGF23 co-receptor Klotho is expressed weakly in the proximal tubules despite the fact that the FGF23 phosphaturic action is substantially exerted at this levelwhereas distal tubules showed more abundant Klotho expression.
