Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway

Abstract

NG. Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway. Am J Physiol Renal Physiol 292: F148 --F157, 2007. First published August 29, 2006; doi:10.1152/ajprenal.00261.2006.-Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The antiapoptotic action of the heme oxygenase (HO) system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of two-kidney, one-clip (2K1C) rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with Ϸ5 ϫ 10 9 colony-forming units/ml of retrovirus containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After 3 mo, a 0.25-mm U-shaped silver clip was placed around the left renal artery. Animals were killed 3 wk later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of cyclooxygenase 2 (COX-2) and higher 3-nitrotyrosine (3-NT) content as well as increased expression of the proapoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xl, while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with cobalt protoporphyrin resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model. heme oxygenase; hypertension; 2K1C; apoptosis; oxidative stress HEME OXYGENASE (HO) CATALYZES the rate-liming step in heme degradation, producing iron, carbon monoxide (CO), and biliverdin, which is rapidly converted to bilirubin. Two major HO isoforms, the products of two distinct genes, have been described: HO-1, an inducible isoform, and HO-2, a constitutively expressed isoform. HO-1 is induced by heme and a variety of nonheme stimuli, including heavy metals, reactive oxygen species (ROS), nitric oxide (NO), ANG II, endotoxin, and cytokines (1, 2). In general, upregulation of HO-1 serves as an adaptive and beneficial response to these stimuli.Induction of HO-1 has been shown to play a cytoprotective role in renal injury secondary to rhabdomyolysis (32), ischemia-reperfusion injury (31), glomerulonephritis (16), renal transplant rejection (7), and nephrotoxins (e.g., cisplatin) (4). Under these conditions, the protective effects of HO were related to degradation of the toxic free-heme moiety and stimulation of efflux of prooxidant iron from the cells, and also to the biological actions of bilirubin, a potent antioxidant (41) and CO, a vasodilatory and anti-infla...

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

“…Moreover, apoptotic cells were reduced in IRI mice treated with GTCs (P,0.05), suggesting an antiapoptotic effect of GTCs on tubular cells ( Figure 7G). In association with this result, we found that the number of tubules expressing hemeoxygenase-1 (HO-1), a well known protective enzyme that exerts an activity against oxidative stress, 31 was increased in GTCtreated mice ( Figure 7F) compared with mice injected with PBS (P,0.01), and this result was also confirmed by real-time PCR analysis (P,0.05) (Supplemental Figure 5A). Cell proliferation and CD18 + infiltration did not show any difference in GTCs or PBS injected mice (Supplemental Figure 5, B and C).…”

“…31,49 The expression of HO-1 is always correlated with a better prognosis after ischemic damage. [50][51][52] We found that mice injected with GTCs showed a strong upregulation of HO-1 2 days after renal damage induction.…”

Heme oxygenase: the key to renal function regulation

“…Heme-induced renal vasodilation, which increased renal blood flow, was a COX-dependant response, whereas heme-induced diuresis and natriuresis were HO-dependant responses, involving inhibition of tubular reabsorption of water and sodium (160). Upregulation of HO activity resulted in the normalization of blood pressure and the increased expression of antiapoptotic molecules in 2K1C renovascular hypertension (139). ANG-II-mediated induction of HO-1 in vitro and in vivo suggests a HO-1 regulatory role in renal protection as recently described in a study of paraquat and ANG II-mediated tubulointerstitial injury and the resultant salt-sensitive hypertension (150,193).…”

Lentiviral-Human Heme Oxygenase Targeting Endothelium Improved Vascular Function in Angiotensin II Animal Model of Hypertension

“…Thus, the HO system might serve an important protective role in the cardiovascular system against the harmful effects of Ang IIinduced oxidative stress (Pflueger et al, 2005). In the rat kidney, HO-1 is expressed mainly in the renal medulla, where it plays an important role in maintaining blood flow to the renal medulla (Olszanecki et al, 2007). Our previous studies indicate that adenovirus-and retrovirus-mediated overexpression of HO-1 blunts Ang II-induced oxidative damage and hypertension and that pharmacological induction of HO-1 with cobalt protoporphyrin attenuated the increase in blood pressure in a model of renovascular hypertension (Botros et al, 2005).…”

“…In addition, lentivirus-VECAD-HO-1-antisense (AS) transgenic rats were generated to achieve genetic suppression of HO-1, which was accomplished by delivery of the lentivirus-VECAD-HO-1 gene in the AS orientation using Lenti-VECAD for rat AS (rat HO-1-AS) to newborn SpragueDawley rats as described previously Olszanecki et al, 2007).…”