Effect of 2-Hydroxypropyl-γ-cyclodextrin on Renal Inflammation in Alport Mouse Model

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate hydrophobic molecules such as cholesterol. Hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic heptasaccharide, has gained attention as a protective agent for chronic kidney diseases, particularly the genetic kidney disease Alport syndrome, due to its anti-inflammatory property and the ability to reduce cholesterol content in Alport kidneys. However, HP-β-CD has side effects of hearing loss and kidney injury. These concerns are important issues for Alport syndrome patients who have pre-existing hearing abnormalities and kidney dysfunction. We previously revealed that 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide, is less toxic than HP-β-CD. Here, we examined the dose-dependent effects of HP-γ-CD (0.71, 1.42, 2.85 mmol/kg, once a week) on the progressive disease phenotype in the Alport mouse model (Col4a5-G5X). HP-γ-CD at 0.71 mmol/kg suppressed the renal inflammation, glomerulosclerosis, and tubular injury in Alport mice, but did not prevent the decline in kidney function. Moreover, HP-γ-CD at 2.85 mmol/kg increased proteinuria and decreased the body weight of Alport mice. Interestingly, HP-γ-CD did not reduce the unesterified cholesterol (UC) content in Alport mouse kidneys, especially in the glomeruli. These results suggested that HP-γ-CD exerted its anti-inflammatory effect, but did not improve the progressive phenotype in the Col4a5 G5X Alport mouse model. Our findings add more information on the use and dosage effects of HP-γ-CD for experimental Alport syndrome.