FP273
FIBROBLAST GROWTH FACTOR 23 IMPEDES ANGIOTENSIN RECEPTOR BLOCKADE EFFICACY IN EXPERIMENTAL RENAL FIBROSIS

Introduction and Aims: Elevated levels of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) are strongly associated with both morbidity and mortality in CKD patients. It has been hypothesized that FGF23 may interact with the renin-angiotensin system (RAS), increasing resistance to RAS blockade-based treatment and contributing to negative outcomes. We explored this potential interaction between FGF23 and RAS-blockade efficacy in a mouse model of renal fibrosis.

Methods: Unilateral ureteral obstruction (UUO) mice were treated with mouse recombinant FGF23 (160mcg/kg intraperitoneally twice daily) or vehicle, combined with either angiotensin receptor blockade (ARB; losartan, 100mg/L in drinking water) or vehicle. FGF23 treatment was started 3 days prior to UUO surgery. Kidneys were collected 7 days after surgery and were analyzed using quantitative PCR. The contralateral kidneys were used to evaluate pharmacological interactions using the RAS-markers renin, angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor type 1 (AT1r). The effects of FGF23 on renoprotection were studied in the UUO kidneys using the renal damage markers MCP-1, TNF- α, collagen-1, and lipocalin-2 (NGAL). Statistics were performed using the Kruskal-Wallis and Mann-Whitney U tests.

Results: ARB treatment induced a strong increase in renin gene expression compared to UUO/vehicle (median [IQR]: 18.03 [14.91-18.62] vs 1.05 [0.68-1.99], p<0.001), as well as rises in ACE 0.75 [0.59-1.01] vs 1.50 [0.88-1.71], p<0.05) and AT1r expression (0.70 [0.55-1.01] vs 1.35 [1.08-2.09], p<0.05). Mice receiving both FGF23 and ARB displayed a less pronounced rise in renin (12.46 [8.71-16.87], p<0.05 vs ARB). Additionally, co-treatment with FGF23 and ARB resulted in a significantly lower expression of ACE (0.55 [0.38-0.79], p<0.01) and AT1r (0.74 [0.58-1.12, p<0.05) than treatment with ARB only. Furthermore, ACE2 expression levels were lower in the FGF23/ARB group than in the ARB group (1.49 [1.21-2.07] vs 1.87 [1.40-2.79], p<0.05).

ARB treatment reduced renal MCP-1 (0.95 [0.69-1.15] vs 1.91 [1.17-2.11], p<0.01), TNF-α (0.013 [0.010-0.020] vs 0.027 [0.022-0.033], p<0.05), collagen-1 (13.8 [12.1-15.9] vs 24.7 [20.1-32.3], p<0.01) and NGAL (9.8 [7.7-13.1] vs 15.9 [12.1-19.0], p<0.05) compared with vehicle treatment. The reduction of MCP-1 expression by ARB was attenuated by co-treatment with FGF23 (1.36 [0.99-1.52]; p<0.05 vs ARB). Similar non-significant trends were observed for TNF-α (0.023 [0.012-0.024]), collagen-1 (16.6 [11.7-21.3]) and NGAL (11.0 [8.7-12.6]).

Conclusions: In experimental renal fibrosis, the pharmacological and renoprotective effects of angiotensin receptor blockade were partially reversed by co-administration of FGF23. Future studies should address whether FGF23-lowering strategies may enhance RAS-blockade efficacy.