Urinary FABP1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury

Abstract

Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte-or in a PTEC-specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function.

Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy

“…We further compared expression and pathway activity of kidney injury markers across different segments between Con and AAN groups. Four kidney injury markers Fabp1 ( 43 ), Havcr1 ( Kim1 ) ( 44 ), Lcn2 ( 45 ) and Timp2 ( 46 ) were upregulated in AAN ( Figure 4G ). More importantly, AAN group not only showed upregulation of adult tubular stem cell markers Cd24a ( Cd24 ) and Prom1 ( Cd106 ) ( 44 ), but also reactivated nephron progenitor markers Sall1 ( 47 ) and Pax2 ( 44 ).…”

Echinocystic acid prevents obesity and fatty liver via interacting with FABP1

“…Dysregulated FABPs have been associated with numerous diseases, including obesity and NAFLD (Thumser et al, 2014), cardiovascular risk, and cancer. FABP1 is a liver‐specific FABP that plays an important role in lipid metabolism of the liver (Kawakami et al, 2021). Previous studies have shown that knockdown of FABP1 markedly blocked lipid accumulation in hepatocytes (Wu et al, 2016).…”