Abstract
Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease is associated with decreased NO availability and less renal H 2 S production. We hypothesized that combined depletion of NO and H 2 S aggravates hypertension and renal injury. Male 8-wk old Sprague Dawley rats were treated with vehicle, NO synthase inhibitor L-NG-nitroarginine (LNNA; 125 mg/L in drinking water), cystathionine-γ-lyase (CSE) inhibitor propargylglycine (PAG; 37.5 mg/kg BW ip daily) or LNNA + PAG for 1 and 4 weeks (6 rats/group). LNNA after 4w increased systolic blood pressure (SBP; 223±10 vs . 137±3 mmHg in controls; P<0.01), proteinuria (144±35 vs. 17±2 mg/d; P<0.01), uremia (16.6±4.2 vs . 7.0±0.4 mmol/L; P<0.05) and tubulo-interstitial injury (P<0.01). LNNA reduced urinary NO metabolite (NOx) excretion by ∼85% after 1w and 4w. PAG alone had no effect on SBP, renal function or injury, but did reduce urinary NOx excretion. Co-treatment with PAG ameliorated LNNA-induced hypertension (182±10 mmHg; P<0.01) and prevented proteinuria (27±3 mg/d), uremia (8.3±0.4 mmol/L) and tubulo-interstitial injury, but did not further reduce urinary NOx excretion. Renal H 2 S production was almost absent in all PAG groups after 1w and 4w (P<0.01) and was reduced in LNNA-treated rats after 4w (4.6±1.4 vs . 9.2±0.5 μmol/hr/mg; P<0.01). Renal HO-1 gene expression was strongly induced in all PAG-treated groups after 1w and 4w (4 to 19-fold; P<0.01) whereas LNNA only increased HO-1 gene expression at 4w (P<0.01). Immunohistochemistry showed that renal HO-1 protein was primarily interstitial in all PAG-treated groups at 1w and 4w. In contrast, LNNA only showed HO-1 in tubular epithelium in conjunction with protein casts. Depleting NO caused hypertension and renal damage followed by reduced renal H 2 S production and increased renal HO-1 expression. Surprisingly, concomitant inhibition of CSE ameliorated hypertension and prevented renal injury. PAG almost completely blocked renal H 2 S production and caused strong induction of renal HO-1, independently of injury, suggesting that H 2 S suppresses renal HO-1 expression. In conclusion, concomitant upregulation of HO-1 expression by inhibition of H 2 S production, prevents LNNA-induced hypertension and renal injury.
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