A9684 Comparing anti-fibrotic effects of the irap inhibitor, hfi-419 to an angiotensin receptor blocker and ace inhibitor in a high salt-induced mouse model of kidney disease

Objectives: To compare the anti-fibrotic effects of the IRAP inhibitor, HFI-419 to the AT1 receptor blocker, Candesartan cilexetil (CAND) or ACE inhibitor, Perindopril (PERIN) in a murine high salt (HS) diet-induced model of kidney disease. Methods: 8–10 week male C57Bl/6J mice were subjected to 8-weeks of HS (5% NaCl) diet-induced renal injury. From weeks 5–8, sub-groups (n = 4–8) were treated with either vehicle, HFI-419 (0.72 mg/kg/d), CAND (2 mg/kg/day) or PERIN (4 mg/kg/d). Mice maintained on a normal salt (NS) diet (0.5% NaCl) for 8-weeks were used as controls. Various measures of renal inflammation and fibrosis as well as plasma urea levels were evaluated. Results: HS diet-fed mice demonstrated increased renal inflammation, glomerulosclerosis, interstitial fibrosis, myofibroblast differentiation and TGF-β1 expression (as determined by morphometry of Masson's trichrome- or immunohistochemically-stained sections and/or Western blotting), total kidney collagen concentration (hydroxyproline analysis), TIMP-1 expression and plasma urea compared to that measured from NS diet-fed counterparts (all P < 0.01 vs NS group). HFI-419 significantly reduced several measures of renal fibrosis as well as plasma urea levels back to that measured in NS diet-fed mice (all p < 0.05 vs HS group). These effects were similar to the anti-fibrotic effects demonstrated with PERIN. However, PERIN worsened plasma urea levels at the dose used (p < 0.01 vs HS group). Interestingly CAND did not demonstrate any marked anti-fibrotic effects in this model. Conclusion: These findings suggest the HFI-419 offers improved anti-fibrotic efficacy and renoprotection compared to CAND and safer anti-fibrotic efficacy compared to PERIN in the setting of HS-induced kidney damage.