Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that carbon monoxide (CO), which is formed by the enzyme heme oxygenase (HO) during the conversion of heme to biliverdin, shares some of the chemical and biological properties of nitric oxide (NO) and may play roles similar to those of NO. Heme oxygenase activity in the kidney has been reported for many years, and there are some reports on the expression of mRNA for two HO isozymes (HO-1 and HO-2) and cellular localization of HO-1 protein. However, cellular localization of HO-2 protein in the kidney under normal conditions has not been reported. In the present study we examined the expression and distribution of HO-2 mRNA and HO-2 protein in rat kidney using RNA protection assay and light and electron immunocytochemistry. RNA protection assay confirmed constitutive expression of HO-2 transcript in rat kidney. HO-2 immunoreactivity was selectively found in epithelial cells of the thick ascending limb and distal convoluted tubule, connecting tubule cells, and principal cells of the collecting duct. These results suggest that HO-2 is synthesized in the kidney and that HO-2 in the epithelial cells of renal tubules may serve as a source for CO generation under normal conditions.
 ...
PMID:Expression and distribution of heme oxygenase-2 mRNA and protein in rat kidney. 944 32

Epithelial cells derived from the mammalian kidney medulla are responsive to urea at the levels of signal transduction and gene regulation. Hybridization of RNA harvested from control- and urea-treated murine inner medullary collecting duct (mIMCD3) cells with a cDNA expression array encoding stress-responsive genes suggested that heme oxygenase (HO)-1 mRNA was upregulated by urea. RNase protection assay confirmed this upregulation; hypertonicity also increased HO-1 mRNA expression but neither hypertonic NaCl nor urea were effective in the nonrenal 3T3 cell line. The effect on HO-1 expression appeared to be transcriptionally mediated on the basis of mRNA half-life studies and reporter gene analyses using the promoters of both human and chicken HO-1. Although urea signaling resembles that of heavy metal signaling in other contexts, the effect of urea on HO-1 transcription was independent of the cadmium response element in this promoter. Urea-inducible HO-1 expression was sensitive to antioxidants but not to scavengers of nitric oxide. Urea also upregulated HO-1 protein expression and pharmacological inhibition of HO-1 action with zinc protoporphyrin-sensitized mIMCD3 cells to the adverse effects of hypertonicity but not to urea. Coupled with the prior observation of others that HO-1 expression increases along the renal corticomedullary gradient, these data suggest that HO-1 expression may comprise an element of the adaptive response to hypertonicity and/or urea in renal epithelial cells.
 ...
PMID:Urea and hypertonicity increase expression of heme oxygenase-1 in murine renal medullary cells. 1159 56

Induction of heme oxygenase-1 (HO-1) in renal tubules occurs as an adaptive and beneficial response in acute renal failure (ARF) following ischemia and nephrotoxins. Using an in vitro model of polarized Madin-Darby canine kidney (MDCK) epithelial cells, we examined apical and basolateral cell surface sensitivity to HO-1 induction by heme. Basolateral exposure to 5 microM hemin (heme chloride) resulted in higher HO-1 induction than did apical exposure. The peak induction of HO-1 by basolateral application of hemin occurred between 12 and 18 h of exposure and was dose dependent. Similar cell surface sensitivity to hemin-induced HO-1 expression was observed using a mouse cortical collecting duct cell line (94D cells). Hepatocyte growth factor (HGF) is known to decrease cell polarity of MDCK cells. Following pretreatment with HGF, apically applied hemin gave greater stimulation of HO-1 expression, whereas HGF alone did not induce HO-1. We also examined the effect of hypoxia on hemin-mediated HO-1 induction. MDCK cells were subjected to hypoxia (1% O(2)) for 24 h to simulate the effects of ischemic ARF. Under hypoxic conditions, both apical as well as basolateral surfaces of MDCK were more sensitive to HO-1 induction by hemin. Hypoxia alone did not induce HO-1 but appeared to potentiate both apical and basolateral sensitivity to hemin-mediated induction. These data demonstrate that the induction of HO-1 expression in polarized renal epithelia by heme is achieved primarily via basolateral exposure. However, under conditions of altered renal epithelial cell polarity and hypoxia, increased HO-1 induction occurs following apical exposure to heme.
 ...
PMID:Epithelial cell polarity and hypoxia influence heme oxygenase-1 expression by heme in renal epithelial cells. 1662 74

Induction of heme oxygenase-1 (HO-1) in the renal medulla increases carbon monoxide and bilirubin production and decreases ANG II-mediated superoxide production. The goal of this study was to determine the importance of increases in bilirubin to the antioxidant effects of HO-1 induction in cultured mouse thick ascending loop of Henle (TALH) and inner medullary collecting duct (IMCD3) cells. Bilirubin levels were decreased by using small interfering RNAs (siRNAs) targeted to biliverdin reductase (BVR), which is the cellular enzyme responsible for the conversion of biliverdin to bilirubin. Treatment of cultured TALH or IMCD-3 cells with BVR siRNA (50 or 100 nM) resulted in an 80% decrease in the level of BVR protein and decreased cellular bilirubin levels from 46 +/- 5 to 23 +/- 4 nM (n = 4). We then determined the effects of inhibition of BVR on ANG II-mediated superoxide production. Superoxide production induced by ANG II (10(-9) M) significantly increased in both TALH and IMCD-3 cells. Treatment of TALH cells with BVR siRNA resulted in a significant increase in ouabain-sensitive rubidium uptake from 95 +/- 6 to 122 +/- 5% control (n = 4, P < 0.05). Lastly, inhibition of BVR with siRNA did not prevent the decrease in superoxide levels observed in cells pretreated with the HO-1 inducer, hemin. We conclude that decreased levels of cellular bilirubin increase ANG II-mediated superoxide production and sodium transport; however, increases in bilirubin are not necessary for HO-1 induction to attenuate ANG II-mediated superoxide production.
 ...
PMID:Inhibition of biliverdin reductase increases ANG II-dependent superoxide levels in cultured renal tubular epithelial cells. 1975 34

We used the patch-clamp technique to examine the role of carbon monoxide (CO) in regulating Ca(2+)-activated big-conductance K (BK) channels in the principal cell of the cortical collecting duct (CCD). Application of CORM3 or CORM2, a CO donor, activated BK channels in the CCD, whereas adding inactivated CORM2/3 had no effect. Superfusion of the CCD with CO-bubbled bath solution also activated the BK channels in the cell-attached patches. The effect of CO on BK channels was not dependent on nitric oxide synthase (NOS) because the effect of CORM3 was also observed in the CCD treated with l-NAME, an agent that inhibits the NOS. Adding a membrane-permeable cGMP analog, 8-bromo-cGMP, significantly increased the BK channel in the CCD. However, inhibition of soluble guanylate cyclase failed to abolish the stimulatory effect of CORM3 on BK channels. Moreover, inhibition of cGMP-dependent protein kinase G did not block the stimulatory effect of CORM3 on the BK channels, suggesting that the stimulatory effect of CO on the BK channels was, at least partially, induced by a cGMP-independent mechanism. Western blot demonstrated that heme oxygenase type 1 (HO-1) and HO-2 were expressed in the kidney. Moreover, a high-K (HK) intake increased the expression of HO-1 but not HO-2 in the kidney. A HK intake also increased renal HO activity defined by NADPH-dependent CO generation following addition of heme in the cell lysate from renal cortex and outer medulla. The role of HO in regulating BK channel activity in the CCD was also suggested by experiments in which application of hemin increased the BK channels. The stimulatory effect of hemin on the BK channels was blocked by SnMP, a HO inhibitor. But, adding CORM3 was still able to activate the BK channels in the presence of SnMP. We conclude that CO activates the BK channels, at least partially, through a NO-cGMP-independent pathway and that HO plays a role in mediating the effect of HK intake on the BK channels in the CCD.
 ...
PMID:Carbon monoxide stimulates Ca2+ -dependent big-conductance K channels in the cortical collecting duct. 2323 81

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson's disease, and LRRK2 is also linked to Crohn's and Hansen's disease. LRRK2 is expressed in many organs in mammals but is particularly abundant in the kidney. We find that LRRK2 protein is predominantly localized to collecting duct cells in the rat kidney, with much lower expression in other kidney cells. While genetic knockout (KO) of LRRK2 expression is well-tolerated in mice and rats, a unique age-dependent pathology develops in the kidney. The cortex and medulla of LRRK2 KO rat kidneys become darkly pigmented in early adulthood, yet aged animals display no overt signs of kidney failure. Accompanying the dark pigment we find substantial macrophage infiltration in LRRK2 KO kidneys, suggesting the presence of chronic inflammation that may predispose to kidney disease. Unexpectedly, the dark kidneys of the LRRK2 KO rats are highly resistant to rhabdomyolysis-induced acute kidney injury compared with wild-type rats. Biochemical profiling of the LRRK2 KO kidneys using immunohistochemistry, proteomic and lipidomic analyses show a massive accumulation of hemoglobin and lipofuscin in renal tubules that account for the pigmentation. The proximal tubules demonstrate a corresponding up-regulation of the cytoprotective protein heme oxygenase-1 (HO-1) which is capable of mitigating acute kidney injury. The unusual kidney pathology of LRRK2 KO rats highlights several novel physiological roles for LRRK2 and provides indirect evidence for HO-1 expression as a protective mechanism in acute kidney injury in LRRK2 deficiency.
...
PMID:Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury. 2590 7

Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor-nuclear factor erythroid 2-related factor 2 (Nrf2)-has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.
 ...
PMID:Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. 3123 73

Downregulation of heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX2), and nitric oxide synthase-2 (NOS2) in the kidneys of Dahl rodents causes salt sensitivity, while restoring their expression aids in Na+ excretion and blood pressure reduction. Loading cholesterol into collecting duct (CD) cells represses fluid shear stress (FSS)-mediated COX2 activity. Thus, we hypothesized that cholesterol represses flow-responsive genes necessary to effectuate Na+ excretion. To this end, CD cells were used to test whether FSS induces these genes and if cholesterol loading represses them. Mice fed either 0% or 1% cholesterol diet were injected with saline, urine volume and electrolytes were measured, and renal gene expression determined. FSS-exposed CD cells demonstrated increases in HO-1 mRNA by 350-fold, COX2 by 25-fold, and NOS2 by 8-fold in sheared cells compared with static cells (P < 0.01). Immunoblot analysis of sheared cells showed increases in HO-1, COX2, and NOS2 protein, whereas conditioned media contained more HO-1 and PGE2 than static cells. Cholesterol loading repressed the sheared mediated protein abundance of HO-1 and NOS2 as well as HO-1 and PGE2 concentrations in media. In cholesterol-fed mice, urine volume was less at 6 h after injection of isotonic saline (P < 0.05). Urinary Na+ concentration, urinary K+ concentration, and osmolality were greater, whereas Na+ excretion was less, at the 6-h urine collection time point in cholesterol-fed versus control mice (P < 0.05). Renal cortical and medullary HO-1 (P < 0.05) and NOS2 (P < 0.05) mRNA were repressed in cholesterol-fed compared with control mice. Cholesterol acts to repress flow induced natriuretic gene expression, and this effect, in vivo, may contribute to renal Na+ avidity.
 ...
PMID:Cellular cholesterol modifies flow-mediated gene expression. 3153 44