{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T10:49:43Z","timestamp":1793875783306,"version":"4.7.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T00:00:00Z","timestamp":1538697600000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:p>\n                    Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end\u2010stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)\u2010induced hepatic and renal injury in mice\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    by using biochemical assays, real\u2010time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time\u2010dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin\u20102, kidney injury molecule 1 (KIM\u20101) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase\u20102 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase\u20102 knockout mice were partially protected from BDL\u2010induced renal injury and had less impairment in microvascular function. In human\u2010cultured proximal tubular epithelial cells hyperammonemia\n                    <jats:italic toggle=\"yes\">per se<\/jats:italic>\n                    induced upregulation of arginase\u20102 and markers of tubular cell injury.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase\u20102 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2018; 00:000\u2010000).\n                  <\/jats:p>","DOI":"10.1002\/hep.29915","type":"journal-article","created":{"date-parts":[[2018,4,9]],"date-time":"2018-04-09T17:12:54Z","timestamp":1523293974000},"page":"1519-1533","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice"],"prefix":"10.1097","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-0784","authenticated-orcid":false,"given":"Zoltan V.","family":"Varga","sequence":"first","affiliation":[{"name":"Laboratory of Cardiovascular Physiology and Tissue Injury,National Institutes of Health\/NIAAA,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Erdelyi","sequence":"additional","affiliation":[{"name":"Laboratory of 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