An acute phase protein α1-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action

Abstract

The molecular mechanism for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) continues to be unclear. In this study, we investigated the pathophysiological role of the acute phase protein α1-acid glycoprotein (AGP) in AKI and its progression to CKD using AGP KO mice. Plasma AGP levels in WT mice were increased by about 3.5-fold on day 1–2 after renal ischemia–reperfusion (IR), and these values then gradually decreased to the level before renal IR on day 7–14. On day 1 after renal IR, the AGP KO showed higher renal dysfunction, tubular injury and renal inflammation as compared with WT. On day 14, renal function, tubular injury and renal inflammation in WT had recovered, but the recovery was delayed, and renal fibrosis continued to progress in AGP KO. These results obtained from AGP KO were rescued by the administration of human-derived AGP (hAGP) simultaneously with renal IR. In vitro experiments using RAW264.7 cells showed hAGP treatment suppressed the LPS-induced macrophage inflammatory response. These data suggest that endogenously induced AGP in early renal IR functions as a renoprotective molecule via its anti-inflammatory action. Thus, AGP represents a potential target molecule for therapeutic development in AKI and its progression CKD.

Serum Plasminogen Activator Inhibitor-1, α 1-Acid Glycoprotein, C-Reactive Protein, and Platelet Factor 4 Levels—Promising Molecules That Can Complete the “Puzzle” of the Biochemical Milieu in Severe Burns: Preliminary Results of a Cohort Prospective Study

“…Furthermore, AGP has an inhibitory action upon platelet aggregation [27]. Some studies demonstrated an anti-inflammatory effect of AGP [29].…”

“…CRP and AGP were cited as biomarkers in the prediction of all-cause mortality [27,28]. Besides the fact that AGP levels increase in systemic inflammation, this molecule has antiinflammatory and immunomodulatory effects [29][30][31], being a well-known inhibitor of neutrophiles and of the complement system [32,33]. AGP has another important function: it binds and transports endogen ligands related to inflammation and many drugs; thus, it is involved in the modulation of pharmacodynamics and pharmacokinetics of medicines [33].…”

Heat acclimation ameliorated heat stress-induced acute kidney injury and prevented changes in kidney macrophages and fibrosis

“…Three-micrometer sections were stained with periodic acid-Schiff reagent (Cosmo Bio, Tokyo, Japan). Tubular injuries were defined as tubular necrosis, cast formation, loss of the brush border, and tubular vacuolization ( 31 ). At least four fields at ×200 magnification from each sample were scored as follows: 0, normal; 1, percentage of injury tubules ≤10%; 2, 11–25%; 3, 26–45%; 4, 46–75%; and 5: ≥75%, as previously described elsewhere ( 31 ).…”

“…Tubular injuries were defined as tubular necrosis, cast formation, loss of the brush border, and tubular vacuolization ( 31 ). At least four fields at ×200 magnification from each sample were scored as follows: 0, normal; 1, percentage of injury tubules ≤10%; 2, 11–25%; 3, 26–45%; 4, 46–75%; and 5: ≥75%, as previously described elsewhere ( 31 ). For the analysis of kidney fibrosis, deparaffinized sections were incubated with picrosirius red solution (Cosmo Bio) for 1 h at room temperature and washed with acetic acid water.…”

The Glomerular Endothelium Restricts Albumin Filtration

“…For instance, urinary excretion of orosomucoid increases in patients with type 2 diabetes and may be a biomarker for EC dysfunction due to low-grade inflammation ( 262 ). In triple (ORM1-3) knockout mice (unlike humans, mice have 3 ORM genes), enhanced inflammation and a greater susceptibility to renal fibrosis in the unilateral ureteral obstruction ( 263 ) and acute ischemia-reperfusion ( 264 ) models have been reported. At this time, quantitative glomerular permselectivity studies in ORM deficient mice are lacking.…”