MO443: Accumulation of REG-1Α in Proximal Tubules of a Rat Model of Chronic Kidney Disease: A New Biomarker at the Interface Between Renal Impairment and Neurodegenerative Diseases

Abstract

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) increases the risk of developing cognitive dysfunction and it has been identified as a modifiable risk factor for Alzheimer's disease (AD) [1]. Regenerating family member 1 alpha (Reg-1α) protein, originally identified as a 16 kDa polypeptide in the pancreas, is increased in cerebrospinal fluid (CSF) and in neurons of AD patients [2, 3]. Reg-1α is also elevated in blood in inflammatory conditions and chronic illnesses such as diabetes and interestingly, in patients with renal function impairment [4, 5]. It is not known whether Reg-1α is synthesized in the kidney or the modifications observed in CKD are merely due to a decline in the glomerular filtration rate. The aim of our study was to localize and quantify the Reg-1α protein in the kidneys of normal rats or CKD rats (5/6 nephrectomized rats) and determine, in a second time, if serum Reg-1α level is a suitable marker for assessment of renal function. As Reg-1a is able to cross the altered blood-brain barrier, it might be a new interesting biomarker at the interface between renal impairment and neurodegenerative diseases. METHOD A total of 16 3-month-old rats were randomly allocated to 5/6 nephrectomy (Nx) or Sham operation. Three months after surgery, serum creatinine and urea, systolic blood pressure (SBP) were measured and renal fibrosis (Sirius Red) was quantified. The expression of Reg-1α was evaluated by double-immunofluorescence using anti-Reg-1α and anti-Aquaporin-1 (Aqp-1) (as a proximal tubule marker) antibodies to determine the localization of Reg-1α in the kidney. RESULTS 5/6Nx rats showed increased serum creatinine levels (97.3 ± 17.6 versus Sham 26.3 ± 0.8 µmol/L; P < 0.05) and serum urea levels (23.9 ± 8.9 versus Sham 4.7 ± 0.1 mmol/L). They also had a higher SBP (158 ± 12 versus Sham 133 ± 5 mmHg) and renal fibrosis increased in the 5/6Nx group (8.1 ± 1.5 versus Sham 2.7 ± 0.2% staining). The double-immunofluorescence revealed an increased expression of Reg-1α of 5/6Nx rats compared with the Sham group. This expression seemed to be specific to the cytoplasm of the proximal tubules, with a ring-shaped distribution (preliminary results, Figure 1). CONCLUSION Our data show, for the first time, a proximal tubule-specific accumulation in Reg-1α in CKD suggesting an influence of impaired renal function on Reg-1α accumulation. Further assessment of Reg-1a in the blood, the blood-brain barrier and neuroinflammation status in this model is needed to better understand the potential effect of kidney accumulation of Reg-1α on brain dysfunction. Should this effect be confirmed, Reg-1α would be a new actor involved in the kidney-brain dialogue.