Christian Herzog

University of Arkansas at Little Rock, Little Rock, Arkansas, United States

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Publications (11)48.95 Total impact

  • Christian Herzog · Raju Marisiddaiah · Randy S Haun · Gur P Kaushal
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    ABSTRACT: Meprins are oligomeric metalloproteinases that are abundantly expressed in the brush-border membranes of renal proximal tubules. During acute kidney injury (AKI) induced by cisplatin or ischemia-reperfusion, membrane-bound meprins are shed and their localization is altered from the apical membranes toward the basolateral surface of the proximal tubules. Meprins are capable of cleaving basement membrane proteins in vitro, however, it is not known whether meprins are able of degrade extracellular matrix proteins under pathophysiological conditions in vivo. The present study demonstrates that a basement membrane protein, nidogen-1, is cleaved and excreted in the urine of mice subjected to cisplatin-induced nephrotoxicity, a model of AKI. Cleaved nidogen-1 was not detected in the urine of untreated mice, but during the progression of cisplatin nephrotoxicity, the excretion of cleaved nidogen-1 increased in a time-dependent manner. The meprin inhibitor actinonin markedly prevented urinary excretion of the cleaved nidogen-1. In addition, meprin β-deficient mice, but not meprin α-deficient mice, subjected to cisplatin nephrotoxicity significantly suppressed excretion of cleaved nidogen-1, further suggesting that meprin β is involved in the cleavage of nidogen-1. These studies provide strong evidence for a pathophysiological link between meprin β and urinary excretion of cleaved nidogen-1 during cisplatin-induced AKI. Published by Elsevier Ireland Ltd.
    No preview · Article · May 2015 · Toxicology Letters
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    ABSTRACT: Meprin A, composed of α and β subunits, is a membrane-bound metalloproteinase in renal proximal tubules. Meprin A plays an important role in tubular epithelial cell injury during acute kidney injury (AKI). The present study demonstrated that during ischemia-reperfusion -induced AKI meprin A was shed from proximal tubule membranes, as evident from its redistribution toward the basolateral side, proteolytic processing in the membranes, and excretion in the urine. To identify the proteolytic enzyme responsible for shedding of meprin A we generated stable HEK cell lines expressing meprin β alone and both meprin α and meprin β for the expression of meprin A. Phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM) stimulated ectodomain shedding of meprin β and meprin A. Among the inhibitors of various proteases, the broad-spectrum inhibitor of the ADAM family of proteases, TAPI-1, was most effective in preventing constitutive, PMA-, and IM-stimulated shedding of meprin β and meprin A in the medium of both transfectants. The use of differential inhibitors for ADAM10 and ADAM17 indicated that ADAM10 inhibition is sufficient to block shedding. In agreement with these results, small interfering RNA to ADAM10 but not to ADAM9 or ADAM17 inhibited meprin β and meprin A shedding. Furthermore, overexpression of ADAM10 resulted in enhanced shedding of meprin β from both transfectants. Our studies demonstrate that ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin β and meprin A. These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI.
    No preview · Article · Mar 2014 · Journal of Biological Chemistry
  • Varsha Kaushal · Christian Herzog · Randy S Haun · Gur P Kaushal
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    ABSTRACT: Members of the caspase family of proteases are evolutionarily conserved cysteine proteases that play a crucial role as the central executioners of the apoptotic pathway. Since the discovery of caspases, many methods have been developed to detect their activation and are widely used in basic and clinical studies. In a mouse tissue, caspase activation can be monitored by cleavage of caspase-specific synthetic substrates and by detecting cleaved caspase by western blot analysis of the tissue extract. In tissue sections, active caspase can be detected by immunostaining using specific antibodies to the active caspase. In addition, among the myriads of caspase-specific substrates known so far, cleaved fragments produced by caspases from the substrates such as PARP, lamin A, and cytokeratin-18 can be monitored in tissue sections by immunostaining as well as western blots of tissue extracts. In general, more than one method should be used to ascertain detection of activation of caspases in a mouse tissue.
    No preview · Article · Feb 2014 · Methods in molecular biology (Clifton, N.J.)
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    Gur P Kaushal · Randy S Haun · Christian Herzog · Sudhir V Shah
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    ABSTRACT: Meprin A, comprised of α and β subunits, is a membrane-associated neutral metalloendoprotease that belongs to the astacin family of zinc endopeptidases. It was first discovered as an azocasein and benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase in the brush-border membranes of proximal tubules and intestines. Meprin isoforms are now found to be widely distributed in various organs (kidney, intestines, leukocytes, skin, bladder, and a variety of cancer cells) and are capable of hydrolyzing and processing a large number of substrates including extracellular matrix proteins, cytokines, adherens junction proteins, hormones, bioactive peptides, and cell surface proteins. The ability of meprin A to cleave various substrates sheds new light on the functional properties of this enzyme including matrix remodeling, inflammation, and cell-cell and cell-matrix processes. Following ischemia-reperfusion (IR)- and cisplatin-induced acute kidney injury (AKI), meprin A is redistributed toward the basolateral plasma membrane and the cleaved form of meprin A is excreted in the urine. These studies suggest that altered localization and shedding of meprin A in places other than the apical membranes may be deleterious in vivo in acute tubular injury. These studies also provide new insight on the importance of a sheddase involved in the release of membrane-associated meprin A under pathological conditions. Meprin A is injurious to the kidney during AKI, as meprin A-knockout mice and meprin inhibition provide protective roles and improve renal function. Meprin A, therefore, plays an important role in AKI and potentially is a unique target for therapeutic intervention during AKI.
    Preview · Article · Feb 2013 · AJP Renal Physiology
  • Christian Herzog · Cheng Yang · Alexandrea Holmes · Gur P Kaushal
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    ABSTRACT: Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.
    No preview · Article · Aug 2012 · AJP Renal Physiology
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    Zhen Wang · Christian Herzog · Gur P Kaushal · Neriman Gokden · Philip R Mayeux
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    ABSTRACT: Sepsis-induced acute kidney injury occurs in 20% to 50% of septic patients and nearly doubles the mortality rate of sepsis. Because treatment in the septic patient is usually begun only after the onset of symptoms, therapy that is effective even when delayed would have the greatest impact on patient survival. The metalloproteinase meprin A, an oligomeric complex made of α- and β-subunits, is highly expressed at the brush-border membranes of the kidney and capable of degrading numerous substrates including extracellular matrix proteins and cytokines. The goal of the present study was to compare the therapeutic potential of actinonin, an inhibitor of meprin A, when administered before and after the onset of sepsis. Mice were treated with actinonin at 30 min before or 7 h after induction of sepsis by cecal ligation and puncture (CLP). Intravital videomicroscopy was used to image renal peritubular capillary perfusion and reactive nitrogen species. Actinonin treatment 30 min before CLP reduced IL-1β levels and prevented the fall in renal capillary perfusion at 7 and 18 h. Actinonin also prevented the fall in renal capillary perfusion even when administered at 7 h after CLP. In addition, even late administration of actinonin preserved renal morphology and lowered blood urea nitrogen and serum creatinine concentrations. These data suggest that agents such as actinonin should be evaluated further as possible therapeutic agents because targeting both the early systemic and later organ-damaging effects of sepsis should have the highest likelihood of success.
    Preview · Article · Feb 2011 · Shock (Augusta, Ga.)
  • Ling Liu · Cheng Yang · Christian Herzog · Rohit Seth · Gur P Kaushal
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    ABSTRACT: We demonstrate the effect of proteasome inhibitors in mitochondrial release of apoptosis-inducing factor (AIF) in cisplatin-exposed renal tubular epithelial cells (LLC-PK(1) cells) and in a model of cisplatin nephrotoxicity. Immunofluorescence and subcellular fractionation studies revealed cisplatin-induced translocation of AIF from the mitochondria to nucleus. Mcl-1, a pro-survival member of the Bcl-2 family, is rapidly eliminated on exposure of renal cells to cisplatin. Proteasome inhibitors PS-341 and MG-132 blocked cisplatin-induced Mcl-1 depletion and markedly prevented mitochondrial release of AIF. PS-341 and MG132 also blocked cisplatin-induced activation of executioner caspases and apoptosis. These studies suggest that proteasome inhibitors prevent cisplatin-induced caspase-dependent and -independent pathways. Overexpression of Mcl-1 was effective in blocking cisplatin-induced cytochrome c and AIF release from the mitochondria. Downregulation of Mcl-1 by small interfering RNA promoted Bax activation and cytochrome c and AIF release, suggesting that cisplatin-induced Mcl-1 depletion and associated Bax activation are involved in the release of AIF. Expression of AIF protein in the mouse was highest in the kidney compared to the heart, brain, intestine, liver, lung, muscle, and spleen. In an in vivo model of cisplatin nephrotoxicity, proteasome inhibitor MG-132 prevented mitochondrial release of AIF and markedly attenuated acute kidney injury as assessed by renal function and histology. These studies provide evidence for the first time that the proteasome inhibitors prevent cisplatin-induced mitochondrial release of AIF, provide cellular protection, and markedly ameliorate cisplatin-induced acute kidney injury. Thus, AIF is an important therapeutic target in cisplatin nephrotoxicity and cisplatin-induced depletion of Mcl-1 is an important pathway involved in AIF release.
    No preview · Article · Sep 2009 · Biochemical pharmacology
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    ABSTRACT: The present study demonstrates that both oligomeric metalloendopeptidase meprin A purified from kidney cortex and recombinant meprin alpha are capable of generating biologically active IL-1beta from its precursor pro-IL-1beta. Amino-acid sequencing analysis reveals that meprin A and meprin alpha cleave pro-IL-1beta at the His(115)-Asp(116) bond, which is one amino acid N-terminal to the caspase-1 cleavage site and five amino acids C-terminal to the meprin beta site. The biological activity of the pro-IL-1beta cleaved product produced by meprin A, determined by proliferative response of helper T-cells, was 3-fold higher to that of the IL-1beta product produced by meprin beta or caspase-1. In a mouse model of sepsis induced by cecal ligation puncture that results in elevated levels of serum IL-1beta, meprin inhibitor actinonin significantly reduces levels of serum IL-1beta. Meprin A and meprin alpha may therefore play a critical role in the production of active IL-1beta during inflammation and tissue injury.
    No preview · Article · Feb 2009 · Biochemical and Biophysical Research Communications
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    Gur P Kaushal · Varsha Kaushal · Christian Herzog · Cheng Yang
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    ABSTRACT: One of the major side effects of cisplatin chemotherapy is toxic acute kidney injury due to preferential accumulation of cisplatin in renal proximal tubule epithelial cells and the subsequent injury to these cells. Apoptosis is known as a major mechanism of cisplatin-induced cell death in renal tubular cells. We have also recently demonstrated that autophagy induction is an immediate response of renal tubular epithelial cell exposure to cisplatin. Inhibition of cisplatin-induced autophagy blocks the formation of autophagosomes and enhances cisplatin-induced caspase-3, -6, and -7 activation, nuclear fragmentation and apoptosis. The switch from autophagy to apoptosis by autophagic inhibitors suggests that autophagy induction was responsible for a pre-apoptotic lag phase observed on exposure of renal tubular cells to cisplatin. Our studies provide evidence that autophagy induction in response to cisplatin mounts an adaptive response that suppresses and delays apoptosis. The beneficial effect of autophagy has a potential clinical significance in minimizing or preventing cisplatin nephrotoxicity.
    Full-text · Article · Jul 2008 · Autophagy
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    C Herzog · R Seth · S V Shah · G P Kaushal
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    ABSTRACT: Meprins are zinc-dependent metalloproteinases that are highly expressed in the brush-border membranes of both the kidney and the intestines. Meprins are capable of proteolytically degrading extracellular matrix proteins, proteolytically processing bioactive proteins, and play a role in inflammatory processes. In this study, the function of meprin A in the acute kidney injury (AKI) model of cisplatin nephrotoxicity was examined. Normal linear localization of meprin A in the brush border membranes of proximal tubules was altered in AKI. The meprin A alpha-subunit was detected in the urine of both control and cisplatin-treated mice. A cleaved product of the meprin A beta-subunit, undetected in the urine of control mice, was found to be significantly increased in the urine during the progression of cisplatin nephrotoxicity. The excretion of this beta-fragment was found to be before the rise in serum creatinine and blood urea nitrogen (BUN) suggesting usefulness as a biomarker for AKI. Pretreatment of mice with a meprin A inhibitor afforded protection from cisplatin nephrotoxicity as reflected by significant decreases in serum creatinine, BUN, and the excretion of kidney injury molecule-1. These decreases in serum and urine biomarkers were accompanied by significant decreases in histologic markers such as leukocyte infiltration and apoptosis. Meprin A appears to be an important therapeutic target and urinary excretion appears to be a potential biomarker of AKI.
    Full-text · Article · Jun 2007 · Kidney International
  • Christian Herzog · Gur P Kaushal · Randy S Haun
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    ABSTRACT: Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that is synthesized as an inactive precursor molecule that must be proteolytically processed to generate the biologically active form. Maturation of the precursor is primarily performed by caspase-1, an intracellular cysteine protease; however, processing by other proteases has been described. Meprins are cell surface and secreted metalloproteases expressed by renal and intestinal brush-border membranes, leukocytes, and cancer cells. In this study we show that purified recombinant meprin B can process the interleukin-1beta precursor to a biologically active form. Amino-terminal sequencing and mass spectrometry analysis of the product of digestion by activated meprin B determined that proteolytic cleavage resulted in an additional six amino acids relative to the site utilized by caspase-1. The biological activity of the meprin B-cleaved cytokine was confirmed by measuring the proliferative response of helper T-cells. These results suggest that meprin may play an important role in activation of this proinflammatory cytokine in various pathophysiological conditions.
    No preview · Article · Oct 2005 · Cytokine