OP26 Renal injury induced by nitric oxide depletion is prevented by concomitant inhibition of hydrogen sulfide and/or carbon monoxide production

Abstract

Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease associates with diminished NO and hydrogen sulfide (H 2 S) availability in the kidney. H 2 S producing cystathionine- γ -lyase (CSE) and carbon monoxide (CO) producing heme oxygenase-1 (HO-1) appear to be protective in mechanical-induced renal injury (e.g. ischemia reperfusion). However, inhibition of CSE can also reduce drug-induced renal injury (e.g. cisplatin or adriamycin). The role of renal H 2 S and HO-1 during chronic NO depletion is unknown. We hypothesized that renal injury secondary to NO depletion caused by inhibition of NO synthase is diminished by additional H 2 S depletion via inhibition of CSE. Rats ( n = 6/group) were treated with inhibitors of NO synthase ( l -nitroarginine; LNNA), CSE (DL-propargylglycine; PAG), or HO-1 (Sn (IV) protoporphyrin IX dichloride; SnPP) for 1 or 4 weeks. Other rats were treated with combinations (LNNA + PAG; LNNA + SnPP; PAG + SnPP or LNNA + PAG + SnPP) for 4 weeks. One week LNNA reduced urinary NOx excretion (35 ± 2%) and induced hypertension (173 ± 12 vs. 137 ± 3 mmHg; P < 0.01) but renal function remained normal. Four weeks of LNNA further reduced urinary NOx (7 ± 1%), worsened hypertension (223 ± 10 mmHg) and caused renal injury, plasma uremia (17 ± 4 vs. 7 ± 1 mmol/L; P < 0.05) and proteinuria (144 ± 35 vs. 17 ± 2 mg/d; P < 0.01). PAG or SnPP had no effect. Interestingly, urine NOx was reduced by PAG and increased by SnPP. Renal H 2 S production was completely blocked by PAG and enhanced by SnPP at 1 and 4 weeks. Renal HO-1 expression was induced by LNNA at 4 weeks and by PAG and SnPP at 1 and 4 weeks (all P < 0.001). Adding PAG, SnPP, or both, to LNNA did not affect hypertension but maintained renal function. Combining PAG and SnPP had no effect on blood pressure and renal function. Strong reduction of urine NOx by LNNA was not affected by additional PAG (8 ± 2%) but was ameliorated by adding SnPP (37 ± 4%) or PAG + SnPP (42 ± 9%). Renal H 2 S production remained completely inhibited with all PAG-combinations ( P < 0.01), but was twofold enhanced by LNNA + SnPP ( P < 0.01). Renal HO-1 expression was increased by all combinations. NO depletion resulted in hypertension and progressive renal injury, while depletion of H 2 S and CO had no effect on blood pressure and kidney function. As hypothesized, renal injury characteristic of NO depletion was prevented by concomitant inhibition of CSE. Interestingly, concomitant inhibition of HO-1 achieved the same result. These data suggest that pathways from NO depletion to renal injury run via H 2 S or CO.