Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Abstract

Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (13963 versus 15362 mmHg in the transgenic and control mice, respectively; P,0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments,. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to biliverdin, during which both carbon monoxide (CO) gas and free iron are released. Biliverdin is then reduced to bilirubin by the ubiquitous enzyme biliverdin reductase. There are two major isoforms of HO that are responsible for the breakdown of heme, HO-1 and HO-2. HO-2 is the constitutively expressed isoform, whereas HO-1 is inducible by a wide variety of stimuli, including hypoxia, metals, ischemia, and oxidative stress. In the kidney, both isoforms of HO are present, with the highest level of expression of both isoforms in the renal medulla under basal conditions. 1,2 HO enzymes are not only expressed in the renal medulla, but their metabolites, CO and bilirubin, play an important role in the regulation of both renal vascular and tubular function. Renal medullary infusion of the general HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol, results in a significant decrease in renal medullary blood flow. 1 In the renal tubules, increases in perfusion pressure increase CO levels, and inhibition of HO activity results in significant attenuation of pressure natriuresis and development of salt-sensitive hypertension. 3

The Baboon Kidney Transcriptome: Analysis of Transcript Sequence, Splice Variants, and Abundance

“…Like CCND1 , CTNNB1 and ERBB2 are also involved in numerous cellular functions and kidney disease [97], [98]. HMOX1 is an essential enzyme involved in the regulation of renal vascular integrity and oxidative stress to reduce or prevent tissue injury in the kidney [99] and has been shown to attenuate the development of angiotensin II-dependent hypertension [100]. Lastly, numerous studies have shown that BCL2L1 plays a key role in the regulation of apoptosis during renal cell injury [101]–[103].…”

Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome

“…This hypothesis is supported by the observation that upregulation of HO-1 expression by both CoPP 157 and SnCl 2 increases mesenteric artery relaxation in spontaneously hypertensive rats (SHR) and decreases the CYP4A-mediated generation of vasoconstrictors by 20-HETE, and that HO-1-derived CO counterbalances 20-HETE mediated vasoconstriction 158 . HO-1 can also regulate renal tubular function by regulating ROS production in renal tubules and by regulation of renal sodium transporters such as the NKCC2 channel of the thick ascending loop of Henle 159 .…”

Renal intramedullary infusion of tempol normalizes the blood pressure response to intrarenal blockade of heme oxygenase-1 in angiotensin II–dependent hypertension

“…For example, induction of HO-1 specifically in the renal medulla via intrarenal medullary interstitial infusion of the HO-1 inducer cobalt protoporyphrin (CoPP) prevented the development of angiotensin II-dependent hypertension (32). Moreover, HO-1 overexpression specifically in thick ascending loop of Henle (TALH) cells in the kidney attenuated the development of angiotensin II-induced hypertension by altering the levels of the sodium, potassium, 2 chloride co-transporter (26). …”