Renal Expression of FGF23 in Progressive Renal Disease of Diabetes and the Effect of Ace Inhibitor

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.

Up-regulation of FGF23 release by aldosterone

“…According to the present observations, the high FGF23 plasma concentration in heart failure [10,11], acute renal failure [12], chronic kidney disease [11,13,14], diabetic nephropathy [15] and hepatic failure [16] could at least in part be secondary to the hyperaldosteronism associated with these diseases. The effect of aldosterone may at least partially be mediated by the serum & glucocorticoid inducible kinase SGK1, which is up-regulated by aldosterone and during diabetes [36] and is known to up-regulate Orai1 [23].…”

“…Excessive plasma FGF23 levels are observed and are associated with accelerated disease progression, morbidity and/or mortality in several clinical disorders including cardiac failure [10,11], acute renal failure [12], chronic kidney disease [11,13,14], diabetic nephropathy [15] and hepatic failure [16]. The pathophysiological significance of enhanced FGF23 formation, has, however, remained ill-defined [17,18] and little is known about mechanisms accounting for the up-regulation of FGF23 release in these clinical disorders.…”

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

“…Whether CKD might affect the expression of FGF23 in these tissues and whether local production, possibly as a compensatory response to tissue injury, significantly augments systemic hormone levels seem worthy of additional investigation. In this regard, it seems particularly noteworthy that renal FGF23 expression has been reported in rodent models of diabetic nephropathy and polycystic kidney disease (87,88).…”

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

“…In patients with cardiac failure [16,17], acute renal failure [18], chronic kidney disease [7,17,19], diabetic nephropathy [20] and hepatic failure [21], plasma FGF23 concentrations are high and associated with accelerated disease progression, morbidity and/or mortality. Mechanisms up-regulating FGF23 in those disorders are still ill-defined.…”