Meprin A Metalloproteinase in Acute Kidney Injury

Summary

Principal Investigator: GUR PRASAD KAUSHAL
Abstract: DESCRIPTION (provided by applicant): Meprins, cell-surface and secreted oligomeric metalloendopeptidases of the 'astacin'family, are highly expressed at the brush-border membranes of the kidney proximal tubules. The specific role of meprins during acute kidney injury (AKI) is not fully understood. Our studies identified that meprin A is the major matrix-degrading protease in the rat kidney cortex capable of degrading the extracellular matrix (ECM) proteins including collagen IV, fibronectin, laminin, and nidogen in vitro. Our recently published and preliminary studies demonstrated that meprins are also capable of producing biologically active proinflammatory cytokine interleukin 1-beta from its inactive proform and proteolytically processing chemotactic cytokine MCP-1, suggesting that meprins are also important in inflammation. Leukocytes isolated from the peripheral blood or the kidney tissue were found to express meprin beta. Furthermore, our studies demonstrate that, following ischemia-reperfusion- and cisplatin-induced AKI, meprin A is redistributed toward the basolateral side of the proximal tubule. These studies suggest that altered localization of meprin A in places other than the apical brush-border membranes may be deleterious in vivo in acute tubular injury. Preliminary studies suggest that meprin A shedding may involve a member of the ADAM (a disintegrin and metalloproteinase) family. Using in vivo models of cisplatin- and ischemia- reperfusion-induced AKI, we demonstrated that actinonin, a potent inhibitor of meprin A inhibits meprin A in vivo and ameliorates acute kidney injury and meprin A-deficient mice are resistant to cisplatin nephrotoxicity. Interestingly, we observed that nidogen and meprin-beta fragments, undetectable in the urine of normal mice, increased significantly during cisplatin nephrotoxicity and actinonin markedly prevented urinary excretion of nidogen fragments. Thus, a unique opportunity exists to further explore the role and mechanism of action of meprin A in AKI. We hypothesize that meprin A, with its enormous destructive potential, is detrimental to renal proximal tubules due to altered localization during AKI and that understanding its mechanism of action is important in protecting or reducing AKI. We will test the hypothesis through the following specific aims: The Specific Aims are: 1. Examine the temporal relationship between meprin A redistribution, renal injury, leukocyte infiltration, and meprin A shedding during AKI using experimental models of IR and cisplatin nephrotoxicity. 2. Identification of meprin A-mediated in vivo degradation products of the ECM components during IR and cisplatin nephrotoxicity. 3. Determine the mechanisms of meprin A-mediated inflammatory effects and functional significance of meprin A during AKI using a meprin inhibitor and meprin A-deficient mice. Understanding the underlying role of meprin A in AKI will provide insights for specific therapeutic interventions to prevent acute kidney injury. PUBLIC HEALTH RELEVANCE: Kidney disease is a frequent and serious disease, which affects 5-7% of all hospitalized patients and 30 % of ICU admissions with a high mortality rate and the expenses related for patients with kidney failure are estimated at $10 billion per year. The risk of mortality is greater than 60% among patients who develop AKI and subsequently require hemodialysis. There has been little improvement in mortality over the last four decades. The mechanisms underlying the causes of kidney injury remain poorly defined. The studies proposed in this application are aimed directly at understanding these mechanisms, which will result in appropriate therapeutic interventions.
Funding Period: 2010-03-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains
    Vishnu C Ramani
    University of Arkansas for Medical Sciences, Departments of Physiology and Biophysics, Little Rock, AR 72205, USA
    Biochim Biophys Acta 1813:1525-31. 2011
  2. pmc zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function
    Christian Herzog
    Department of Medicine, Central Arkansas Veterans Healthcare System, 4300 W 7th St, Little Rock, AR 72205, USA
    Am J Physiol Renal Physiol 303:F1239-50. 2012
  3. pmc Meprin A metalloproteinase and its role in acute kidney injury
    Gur P Kaushal
    Central Arkansas Veterans Healthcare System, 4300 West 7th St, 111D LR, Little Rock, AR 72205, USA
    Am J Physiol Renal Physiol 304:F1150-8. 2013
  4. pmc Caspase protocols in mice
    Varsha Kaushal
    Biology Department, Hendrix College, Conway, AR, USA
    Methods Mol Biol 1133:141-54. 2014
  5. pmc ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
    Christian Herzog
    From the Central Arkansas Veterans Healthcare System and
    J Biol Chem 289:13308-22. 2014

Research Grants

Detail Information

Publications5

  1. pmc Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domains
    Vishnu C Ramani
    University of Arkansas for Medical Sciences, Departments of Physiology and Biophysics, Little Rock, AR 72205, USA
    Biochim Biophys Acta 1813:1525-31. 2011
    ....
  2. pmc zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function
    Christian Herzog
    Department of Medicine, Central Arkansas Veterans Healthcare System, 4300 W 7th St, Little Rock, AR 72205, USA
    Am J Physiol Renal Physiol 303:F1239-50. 2012
    ..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...
  3. pmc Meprin A metalloproteinase and its role in acute kidney injury
    Gur P Kaushal
    Central Arkansas Veterans Healthcare System, 4300 West 7th St, 111D LR, Little Rock, AR 72205, USA
    Am J Physiol Renal Physiol 304:F1150-8. 2013
    ..Meprin A, therefore, plays an important role in AKI and potentially is a unique target for therapeutic intervention during AKI...
  4. pmc Caspase protocols in mice
    Varsha Kaushal
    Biology Department, Hendrix College, Conway, AR, USA
    Methods Mol Biol 1133:141-54. 2014
    ..In general, more than one method should be used to ascertain detection of activation of caspases in a mouse tissue. ..
  5. pmc ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
    Christian Herzog
    From the Central Arkansas Veterans Healthcare System and
    J Biol Chem 289:13308-22. 2014
    ..These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI. ..

Research Grants30

  1. Role of Meprin A in Acute Kidney Injury
    GUR PRASAD KAUSHAL; Fiscal Year: 2013
    ..In addition the study will identify meprin A-mediated urinary markers for early detection of AKI. Therefore, the proposal is clinically relevant to the VA patient population since a large segment of veterans suffer from AKI. ..
  2. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  3. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  5. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..