Abstract 493: Renal Injury Induced by Nitric Oxide Depletion is Prevented by Concomitant Inhibition of Hydrogen Sulfide and/or Carbon Monoxide Production

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Abstract

Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Hydrogen sulfide (H2S) producing cystathionine-γ-lyase (CSE) and carbon monoxide (CO) producing heme oxygenase-1 (HO-1) appear to be protective in mechanically-induced renal injury (e.g. ischemia reperfusion). However, inhibition of CSE can reduce drug-induced renal injury (e.g. cisplatin). The role of renal H2S and HO-1 during chronic NO depletion is unknown. We hypothesized that renal injury secondary to NO depletion via inhibition of NO synthase is diminished by additional H2S 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 or with combinations (LNNA+PAG; LNNA+SnPP; PAG+SnPP or LNNA+PAG+SnPP) for 4 weeks.

One week LNNA reduced urinary NOx excretion (35±2% vs baseline) and induced hypertension (173±12 vs. 137±3 mmHg; P<0.01) but renal function remained normal. Four weeks of LNNA further reduced NOx (7±1%), worsened hypertension (223±10 mmHg) and caused renal injury; plasma urea (17±4 vs 7±1 mmol/L; P<0.05), proteinuria (144±35 vs 17±2 mg/d; P<0.01). PAG or SnPP had no effect. NOx was reduced by PAG and increased by SnPP. Renal H2S 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 preserved renal function. Combining PAG and SnPP had no effect on blood pressure or renal function. 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 H2S production was 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 that was prevented by concomitant inhibition of CSE and/or HO-1. Depletion of H2S and CO in the absence of NO depletion had no effect on blood pressure and renal function. These data suggest that pathways from NO depletion to renal injury run via H2S or CO.

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