Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart

High potassium intake is known to attenuate hypertension, glomerular lesion, ischemic damage, and stroke-associated death. Our recent studies showed that expression of recombinant kallikrein by somatic gene delivery reduced high blood pressure, cardiac hypertrophy, and renal injury in hypertensive animal models. The aim of this study is to explore the potential role of the tissue kallikrein-kinin system in blood pressure reduction and renal protection in spontaneously hypertensive rats (SHR) on a high-potassium diet. Young SHR were given drinking water with or without 1% potassium chloride for 6 wk. Systolic blood pressure was significantly reduced beginning at 1 wk, and the effect lasted for 6 wk in the potassium-supplemented group compared with that in the control group. Potassium supplement induced 70 and 40% increases in urinary kallikrein levels and renal bradykinin B2 receptor density, respectively ( P < 0.05), but did not change serum kininogen levels. Similarly, Northern blot analysis showed that renal kallikrein mRNA levels increased 2.7-fold, whereas hepatic kininogen mRNA levels remained unchanged in rats with high potassium intake. No difference was observed in β-actin mRNA levels in the kidney or liver of either group. Competitive RT-PCR showed a 1.7-fold increase in renal bradykinin B2 receptor mRNA levels in rats with high potassium intake. Potassium supplement significantly increased water intake, urine excretion, urinary kinin, cAMP, and cGMP levels. This study suggests that upregulation of the tissue kallikrein-kinin system may be attributed, in part, to blood pressure-lowering and diuretic effects of high potassium intake.

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High-salt diet upregulates kininogen and downregulates tissue kallikrein expression in Dahl-SS and SHR rats

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.4.f824 ◽

1996 ◽

Vol 271 (4) ◽

pp. F824-F830 ◽

Cited By ~ 5

Author(s):

C. Wang ◽

C. Chao ◽

L. M. Chen ◽

L. Chao ◽

J. Chao

Keyword(s):

Blood Pressure ◽

High Salt ◽

Transcriptional Level ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Hypertensive Rats ◽

High Salt Diet ◽

Salt Loading ◽

Salt Diet ◽

Sd Rats

Tissue kallikrein cleaves low-molecular-weight (low-M(r)) kininogen to produce the vasoactive kinin peptide. It has been suggested that hypertensive patients with low urinary kallikrein excretion may have a defect in sodium handling. In this study, we examined the effect of a high-salt diet on the expression of tissue kallikrein and kininogen genes in Dahl salt-sensitive rats (Dahl-SS), spontaneously hypertensive rats (SHR), and normotensive Sprague-Dawley rats (SD) by Northern and Western blot analysis and radioimmunoassay. Control and experimental groups received normal and high-salt diets containing 0.4% and 8% NaCl, respectively, for 6 wk. High-salt diet induced a significant time-dependent increase of blood pressure in both strains of hypertensive rats and a slight but significant increase of blood pressure in normotensive SD rats. Hepatic kininogen mRNA levels of both Dahl-SS and SHR on a high-salt diet increased 2.4-fold and 2.0-fold, respectively, while alpha 1-antitrypsin mRNA levels were not changed in rats receiving high-salt diet. Immunoreactive total kininogen and low-M(r) kininogen (58 kDa) levels in sera increased in response to high-salt diet in both strains of hypertensive rats. In SD rats, the low-M(r) kininogen level in sera was unaltered, whereas total kininogen increased in response to high-salt diet. Tissue kallikrein mRNAs in the kidney and salivary glands of Dahl-SS, SHR, and SD rats were reduced, whereas beta-actin mRNA was not altered by high-salt diet. Similarly, immunoreactive intrarenal kallikrein levels were reduced in these rats in response to high-salt diet. These studies show that increases in blood pressure after salt loading in Dahl-SS and SHR are accompanied by increases in low-M(r) kininogen. Tissue kallikrein gene expression in hypertensive Dahl-SS and SHR and normotensive SD rats is suppressed after salt loading. These findings show that reduced renal kallikrein expression and increased kininogen expression is regulated at the transcriptional level during salt loading.

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Developmentally regulated kallikrein enzymatic activity and gene transcription rate in maturing rat kidneys

AJP Renal Physiology ◽

10.1152/ajprenal.1993.265.1.f146 ◽

1993 ◽

Vol 265 (1) ◽

pp. F146-F150 ◽

Cited By ~ 2

Author(s):

S. S. el-Dahr ◽

I. Yosipiv

Keyword(s):

Gene Transcription ◽

Transcription Rate ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Female Rat ◽

Kinin System ◽

Transcription Analysis ◽

Renal Kallikrein ◽

Kallikrein Activity ◽

Rat Kidneys

Kinins are paracrine vasoactive and growth-modulating peptides. Kidney maturation is accompanied by enhanced accumulation of the mRNA encoding tissue (renal) kallikrein, a serine protease, and a key component of the kallikrein-kinin system. To further delineate the developmental regulation of renal kallikrein, we measured tissue kallikrein activity and gene transcription rate during the latter stages of metanephrogenesis. Active tissue kallikrein was measured in renal homogenates by the amidolytic assay using the fluorogenic substrate D-Val-Leu-Arg-7-amino-4-methylcoumarin (D-VLR-AMC) in the presence or absence of soybean trypsin inhibitor (SBTI). Kallikrein activity was detectable at very low levels in the near-term fetal metanephros. Postnatally, renal kallikrein activity peaked immediately after birth and again at the time of weaning (P < 0.05 vs. other age groups) and remained high in the adult. Mature female rat kidneys contained 30% more active kallikrein than male kidneys (P < 0.05). The SBTI-sensitive D-VLR-AMC hydrolytic activity (due to serine proteases other than tissue kallikrein) accounted for 36-53% of the total renal amidolytic activity. Compared with the 5-day-old newborn, steady-state renal kallikrein mRNA levels increased threefold by day 12 and sixfold by adulthood. Run-on transcription analysis of renal cell nuclei revealed a significant increase in kallikrein gene transcription rate of 80% on day 12 (P < 0.05) and 480% in the adult (P < 0.001). The presence of active kallikrein in the developing kidney and the upregulation of its synthesis at specific time points during postnatal development implicate intrarenal kinins as potential modulators of renal growth and functional maturation.(ABSTRACT TRUNCATED AT 250 WORDS)

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Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00379.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. L1127-L1140 ◽

Cited By ~ 1

Author(s):

Melia Magnen ◽

Fabien Gueugnon ◽

Agnès Petit-Courty ◽

Thomas Baranek ◽

Damien Sizaret ◽

...

Keyword(s):

Nk Cells ◽

Influenza Virus Infection ◽

Lung Epithelial Cells ◽

H3n2 Virus ◽

Chronic Obstructive ◽

Virus Infectivity ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Copd Patients ◽

Deficient Mice

Host cell proteases are involved in influenza pathogenesis. We examined the role of tissue kallikrein 1 (KLK1) by comparing wild-type (WT) and KLK1-deficient mice infected with influenza H3N2 virus. The levels of KLK1 in lung tissue and in bronchoalveolar lavage (BAL) fluid increased substantially during infection. KLK1 did not promote virus infectivity despite its trypsin-like activity, but it did decrease the initial virus load. We examined two cell types involved in the early control of pathogen infections, alveolar macrophages (AMs) and natural killer (NK) cells to learn more about the antiviral action of KLK1. Inactivating the Klk1 gene or treating WT mice with an anti-KLK1 monoclonal antibody to remove KLK1 activity accelerated the initial virus-induced apoptotic depletion of AMs. Intranasal instillation of deficient mice with recombinant KLK1 (rKLK1) reversed the phenotype. The levels of granulocyte-macrophage colony-stimulating factor in infected BAL fluid were significantly lower in KLK1-deficient mice than in WT mice. Treating lung epithelial cells with rKLK1 increased secretion of this factor known to enhance AM resistance to pathogen-induced apoptosis. The recruitment of NK cells to the air spaces peaked 3 days after infection in WT mice but not in KLK1-deficient mice, as did increases in several NK-attracting chemokines (CCL2, CCL3, CCL5, and CXCL10) in BAL. Chronic obstructive pulmonary disease (COPD) patients are highly susceptible to viral infection, and we observed that the KLK1 mRNA levels decreased with increasing COPD severity. Our findings indicate that KLK1 intervenes early in the antiviral defense modulating the severity of influenza infection. Decreased KLK1 expression in COPD patients could contribute to the worsening of influenza.

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Localization and secretion of tissue kallikrein in peptidoglycan-induced enterocolitis in Lewis rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.275.4.g854 ◽

1998 ◽

Vol 275 (4) ◽

pp. G854-G861 ◽

Cited By ~ 3

Author(s):

Antoni Stadnicki ◽

Julie Chao ◽

Iwona Stadnicka ◽

Eric Van Tol ◽

Kuei-Fu Lin ◽

...

Keyword(s):

Intestinal Inflammation ◽

Rnase Protection Assay ◽

Experimental Colitis ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Kinin System ◽

Rnase Protection ◽

Lewis Rats ◽

Kallikrein Kinin System

The plasma kallikrein-kinin system is a mediator of intestinal inflammation induced by peptidoglycan-polysaccharide from group A streptococci (PG-APS) in rats. In this study we investigated the participation of intestinal tissue kallikrein (ITK). Lewis rats were injected intramurally with PG-APS. ITK was visualized by immunohistochemical staining. Cecal ITK concentration was measured by radioimmunoassay, and gene expression was evaluated by RNase protection assay. Kallikrein-binding protein (KBP) was evaluated in plasma by ELISA. Tissue kallikrein was identified in cecal goblet cells in both control and PG-APS-injected rats and in macrophages forming granulomas in inflamed tissues. Cecal ITK was significantly lower in acute and chronic phases of inflammation and in supernatant from in vitro cultures of inflamed cecum. ITK mRNA levels were not significantly different. Plasma KBP levels were significantly reduced in inflamed rats. The presence of tissue kallikrein in macrophages suggests participation in experimental colitis. The decrease of ITK in the inflamed intestine associated with unchanged mRNA levels suggests ITK release during intestinal inflammation.

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Effect of cyclosporin A on the expression of tissue kallikrein, kininogen, and bradykinin receptor in rat

AJP Renal Physiology ◽

10.1152/ajprenal.1997.273.5.f783 ◽

1997 ◽

Vol 273 (5) ◽

pp. F783-F789

Author(s):

Cindy Wang ◽

Philbert Ford ◽

Caroline Chao ◽

Lee Chao ◽

Julie Chao

Keyword(s):

Blood Pressure ◽

Cyclosporin A ◽

Chronic Administration ◽

Tissue Kallikrein ◽

Mrna Levels ◽

Kinin System ◽

Bradykinin Receptor ◽

System Components ◽

Renal Kallikrein ◽

Kallikrein Kinin System

The tissue kallikrein-kinin system is involved in vasodilation and blood pressure regulation. In the present study, we investigated the effects of chronic cyclosporin A (CsA) administration on blood pressure and the expression of tissue kallikrein, kininogen, and bradykinin receptor in normotensive Wistar rats. Chronic administration of CsA significantly increased systolic blood pressure compared with control rats ( n = 6, P < 0.01), although body weight was significantly lower than control rats ( n = 6, P < 0.01). The development of hypertension was accompanied by the altered expression of kallikrein-kinin system components. Immunoreactive renal kallikrein and urinary excretion of tissue kallikrein levels were increased by chronic administration of CsA ( n = 5 or 6, P < 0.05). Levels of N-tosyl-l-phenylalanine chloromethyl ketone-trypsin and kallikrein-releasable kininogens in sera increased in response to chronic CsA treatment ( n = 5 or 6, P < 0.05). Chronic CsA treatment significantly increased renal kallikrein, bradykinin B2 receptor, and hepatic kininogen mRNA levels. The increased levels of tissue kallikrein-kinin system components were accompanied by significant increases in 24-h urine excretion and water intake after chronic CsA treatment ( n = 5, P < 0.05). These results suggest that enhanced activity of the tissue kallikrein-kinin system may compensate for the CsA-induced vasoconstriction and hypertension.

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Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

Biochemical Journal ◽

10.1042/bcj20190591 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3705-3719 ◽

Cited By ~ 2

Author(s):

Avani Vyas ◽

Umamaheswar Duvvuri ◽

Kirill Kiselyov

Keyword(s):

Oxidative Stress ◽

Head And Neck ◽

Transcriptional Activation ◽

Platinum Resistance ◽

Mrna Levels ◽

Strong Positive Correlation ◽

Platinum Compounds ◽

Copper Chelation ◽

Novel Approach ◽

Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

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