Is There a Role for Indoxyl Sulfate in Contributing to Impaired Cognition and Anxiety Following a Hypertensive Pregnancy?

Abstract

Objective Women with hypertensive conditions of pregnancy are at an increased risk of developing Acute Kidney Injury (AKI) which can lead to the progression of chronic kidney disease (CKD). Patients with CKD have impairments in cognition and increases in anxiety and depression. Indoxyl Sulfate (I.S.), a uremic toxin associated with CKD progression, has been reported to contribute to spatial memory impairment. We hypothesized that impairments in learning and memory and anxiety among rats with a previous hypertensive pregnancy (Hemolysis elevated liver enzyme low platelet – HELLP Syndrome) and AKI are accompanied by increased levels of I.S. Study Design On gestational day (GD) 12, sFlt-1 and sEng were infused via mini-osmotic pumps into the abdomen of timed-pregnant Sprague Dawley rats to induce HELLP. A subset of rats underwent either bilateral renal ischemia-reperfusion surgery for 45 minutes on GD18 to induce AKI or a SHAM surgery. Rats were either euthanized on GD19 to assess I.S. levels during pregnancy or at post-partum week (PPW) 15. Between PPW 11-13 rats underwent Barnes Maze and anxiety testing. I.S. concentrations were measured in the circulation and brainstem of rats. Tissue concentrations were normalized to total protein and group comparisons analyzed via statistical analysis where p<0.05 was considered significant. N=9-14 rats/group. Results HELLP and AKI rats displayed hypertension (p<0.05) and kidney injury (p<0.05) relative to NP rats at both time periods. There was a significant group (p=0.04) effect in Barnes maze with NP rats finishing the test significantly faster relative to all other groups by the 5th day of testing (p<0.03). There was a significant difference between groups in anxiety where HELLP+AKI rats spent significantly less time in the open area of the zero maze compared to NP+AKI rats (p=0.02). When the groups were compared there were no changes in circulating I.S. at GD19 (p=0.06) or at PPW15 (p=0.78). Brainstem levels of I.S. during pregnancy were increased in response to AKI and were significantly increased in NP+AKI vs. HELLP rats (p=0.02). However, by PPW15 brainstem levels of I.S. were trending towards an increase among HELLP+AKI rats vs. NP+AKI rats (p=0.06). Conclusion The results from this study suggest that AKI during pregnancy contributes to behavioral deficits, hypertension and imbalances in brainstem I.S. concentrations. We are currently examining other regions of the brain and increasing the N in the I.S. studies (currently n=3-5/group). As I.S. could possibly be one the mechanisms causing impairments in learning and memory after a hypertensive pregnancy complicated by AKI, additional studies to determine if blockade of I.S. results in improvements in cognition and anxiety are planned.