L‐citrulline prevents progression of diabetic nephropathy by reducing arginase activity

Abstract

Since the role of arginase activity in diabetic nephropathy (DN) remains elusive, we compared DN progression at 2 and 16 wk of diabetes in streptozotocin (STZ)-induced WT versus arginase II (AII) KO mice. Our data demonstrate that: 1. Renal arginase activity (RAA) and urinary albumin excretion (UAE) are both elevated (8.1 and 6.1 fold of ctrl) at 2 wk of diabetes in WT mice. 2. By 16 wk, RAA in WT mice decreases to 2.7 fold of ctrl, which may reflect a decline in kidney function, since glomerular/tubular collagen deposits are observed in 16 wk, but not 2 wk diabetic mice. 3. UAE increases to 7.7 fold above ctrl at 16 wk. 4. Elevation of RAA correlates with increased AII, but not AI expression in WT STZ-mice at both 2 and 16 wk. 5. Ctrl and diabetic AII KO mice display reduced RAA levels (0.3 and 0.4 fold) compared to WT ctrl mice. 6. STZ-AII KO mice have significantly lower UAE (3.5 fold of WT ctrl) and renal collagen deposits than STZ-WT mice at 16 wk. 7. Treatment of STZ-WT mice with L-citrulline (L-cit, 50 mg/kg/d oral) markedly reduces early elevation in RAA at 2 wk to 2.07 fold of ctrl, with no decay (2.9 fold) at 16 wk. 8. L-cit reduces elevation of UAE to 1.4 and 2.6 fold of ctrl at 2 and 16 wk of diabetes, respectively, and prevents progression of renal collagen deposits at 16 wk. In summary, AII is involved in DN. L-cit treatment can prevent or delay the progression of DN, by reducing AII activity. (Supported by JDRF Innov.5-2009-468 & R01 NHL70215)