Intersection of Uremic Toxins and Biological Sex in Chronic Kidney Disease Progression

Children with chronic kidney disease (CKD) are at high risk of complications and have a reduced life
expectancy compared to healthy peers. The risk of complications and death increases as CKD progresses to
higher stages. Childhood CKD is often the result of progressive conditions, such as Alport syndrome, that lead
to advanced CKD and kidney failure. Therefore, there is a critical need to identify mechanisms of kidney
disease progression in Alport syndrome and related genetic pediatric kidney diseases. As kidney disease
progresses, reduced kidney function leads to systemic bioaccumulation of uremic toxins, which are toxic
metabolites normally excreted in the urine. Uremic toxins activate the aryl hydrocarbon receptor (Ahr) in the
kidneys and other organs, and accumulating evidence suggests that these molecules are not merely
byproducts of impaired renal function but contribute to CKD progression. Thus, it is essential to understand the
fundamental biological underpinnings of renal clearance of uremic toxins and the effects uremic toxins on the
kidneys themselves.
In a preliminary study, we found that exposure to the uremic toxin indoxyl sulfate exacerbates CKD progression
in Col4a3 knockout mice, a murine model of Alport syndrome, but the effect was sex-specific to males, with
female mice being protected. Sex differences in CKD outcomes are well-known, but the mechanism is unclear.
There is a significant knowledge gap in relation to sex-specific uremic toxin biology, particular the effects of
uremic toxins on the kidneys and sex differences in renal elimination of uremic toxins. In this application we
propose to investigate the sex-specific effects of uremic toxin-mediated Ahr activation on CKD progression and
the role of sex hormones in regulating the renal elimination of uremic toxins. We will manipulate systemic
concentrations of uremic toxins in Col4a3 knockout mice using drugs that promote or inhibit excretion of these
molecules. We will delineate the role of Ahr activation in CKD progression in male and female Col4a3 knockout
by testing the effect of pharmacologic Ahr inhibition on CKD progression in this model, and by generating
congenic Col4a3 knockout mice with high and low ligand-binding affinity Ahr alleles. Finally, we will compare
the renal clearance of uremic solutes in male and female Col4a3 knockout mice and will use orchiectomy and
ovariectomy to determine the role of sex hormones in modulating renal clearance of uremic toxins.

Grant Number: 5P20GM121293-09
NIH Institute/Center: NIH
Principal Investigator: Joseph Alge