endothelin-1 and cobaltiprotoporphyrin

Topics: Animals; Arterial Pressure; Bilirubin; Biliverdine; Boranes; Carbonates; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelin-1; Enzyme Induction; Female; Heme Oxygenase-1; Ischemia; Kidney Glomerulus; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Protoporphyrins; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5-10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14-19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Administration Schedule; Endothelin-1; Endothelium, Vascular; Enzyme Induction; Female; Gestational Age; Heme Oxygenase (Decyclizing); Liver; Placenta; Pre-Eclampsia; Pregnancy; Protoporphyrins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Cyclosporine A (CsA) is the first immunosuppressant used in allotransplantation. Its use is associated with side effects that include nephrotoxicity. This study explored the anatomic structures involved in CsA nephrotoxicity and the effect of heme oxygenase (HO) in preventing CsA injury. Rats were divided into four groups, which were treated with olive oil, CsA (15 mg/kg/day), CsA plus the HO inhibitor (SnMP; 30 microM/kg/day), and with the HO inducer (CoPP; 5 mg/100 g bw). Renal tissue was treated for morphological, biochemical, and immunohistochemical studies. CsA-treated rats showed degenerative changes with renal fibrosis localized mainly around proximal tubules. Collapsed vessels were sometimes seen in glomeruli. No HO-1 expression and increased expression of endothelin-1 (ET-1) were observed in CsA-treated rats compared with controls. In CsA plus SnMP-treated rats, HO-1 expression was further reduced and the morphology was not changed compared to the CsA group, whereas CsA plus CoPP-treated animals again showed normal morphology and with restoration and an increase in HO-1 levels. HO activity and immunohistochemical data showed similar alterations as HO expression. No changes were observed for HO-2 analysis. The observations indicate that HO-1 downregulation and ET-1 upregulation by CsA might be one mechanism underlying CsA-induced nephrotoxicity. Therefore, attempts to preserve HO levels attenuate CsA nephrotoxicity.

Topics: Animals; Cyclosporine; Endothelin-1; Enzyme Induction; Fibrosis; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Immunohistochemistry; Immunosuppressive Agents; Kidney; Male; Metalloporphyrins; Protoporphyrins; Rats; Rats, Sprague-Dawley