Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge

Abstract

Yura RE, Bradley SG, Ramesh G, Reeves WB, Bond JS. Meprin A metalloproteases enhance renal damage and bladder inflammation after LPS challenge. Am J Physiol Renal Physiol 296: F135-F144, 2009. First published October 29, 2008 doi:10.1152/ajprenal.90524.2008.-Meprin metalloproteases, composed of ␣ and/or ␤ subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin ␣ knockout (␣KO), meprin ␤ knockout (␤KO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin ␣KO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin ␤KO mice. Serum cytokine profiles showed lower levels of IL-1␤ and TNF-␣ in the meprin ␣KO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin ␣KO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity. knockout mice; lipopolysaccharide; kidney; metalloproteinase ACUTE RENAL FAILURE (ARF) is a frequent complication of sepsis, a systemic response to infection that often leads to shock and multiple organ failure (49). Intraperitoneal (ip) administration of endotoxin or LPS, a glycolipid component of the gram negative bacterial cell wall, generates a robust host response similar to that observed during sepsis, including elevated blood urea nitrogen (BUN) and creatinine levels, extensive production of proinflammatory mediators (e.g., TNF-␣, IL-1␤), and release of the vasodilator nitric oxide (NO) (15,20,29,54). TNF-␣ is an important mediator of LPSinduced ARF and is also implicated in induction of hypothermia, a hallmark of the rodent response to endotoxemia and a reliable parameter for evaluating the acute effects of LPS (10,19,20,34,37). The injurious effects of LPS are also readily apparent on transurethral administration of LPS, which produces a localized inflammatory response that resembles urinary tract infection (UTI) and consists of extensive leukocyte infiltration, edema, and urothelial disruption in the bladder tissue (17, 43).Meprin metalloproteases are abundantly expressed in the brush-border membranes of kidney proximal tubules as well as secreted into the urinary tract (12, 45). They are also expressed in the intestine, skin, and discrete populations of leukocytes (5,12,...

ADAM10 Is the Major Sheddase Responsible for the Release of Membrane-associated Meprin A

“…In addition, in this mouse model of sepsis, actinonin also prevented the fall in renal capillary perfusion even when administered after the onset of sepsis injury (15). In response to LPS-induced sepsis, meprin A-deficient mice displayed improved renal function and decreased nitric oxide, IL-1␤, and TNF-␣ levels (68), suggesting that meprin A exacerbated renal injury in response to LPS. Recently, meprin was shown to exacerbate ischemia-reperfusion-induced renal injury in male rats.…”

Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease

“…Nonetheless, the lack of systemic inflammation that is evident in the dKO mice upon colitis induction might arise as a result of defective leukocyte movement between the different hematological compartments in response to the intestinal challenge, thereby resulting in greater susceptibility during the progressive phase of the disease. It has also been demonstrated that meprins alter the integrity of epithelial membrane barriers (38). Meprin B cleaves E-cadherin in the adherens junction and disrupts the integrity of the ability of confluent MDCK cells to exclude dextran (23).…”

Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin

“…Meprins have been implicated in several inflammatory diseases, for example, meprin-␤ has been reported to be a candidate gene for diabetic nephropathy in the Pima Indian population (38). In an experimental model of urinary tract infection, meprin A has been shown to enhance renal damage and bladder inflammation after LPS challenge (53). In addition, polymorphisms of the human MEP1A gene have been correlated with inflammatory bowel diseases (5).…”