Cystic kidney diseases are characterized by multiple renal
cysts and are the leading cause of inherited renal disease.
Oxylipins are bioactive
lipids derived from
fatty acids formed via
cyclooxygenase,
lipoxygenase and
cytochrome P450 activity, and are important regulators of renal health and disease.
Oxylipins are altered in nephronophthisis, a type of
cystic kidney disease. To further investigate and to determine whether other
cystic renal diseases share these abnormalities, a targeted lipidomic analysis of renal
oxylipins was performed in orthologous models of
autosomal dominant polycystic kidney disease 1 (Mx1Cre+Pkd1flox/flox mouse) and 2 (Pkd2ws25/- mouse),
autosomal recessive polycystic kidney disease (PCK rat) and nephronophthisis (jck/jck mouse). Kidney
cyclooxygenase oxylipins were consistently higher in all diseased kidneys, even in very early stage disease. On the other hand,
cytochrome P450 epoxygenase derived
oxylipins were lower only in the
autosomal recessive polycystic kidney disease and nephronophthisis models, while
lipoxygenase and
cytochrome P450 hydroxylase derived
oxylipins were lower only in nephronophthisis. Sex effects on renal
oxylipin alterations were observed but they did not always coincide with sex effects on disease. For
oxylipins with sex effects,
arachidonic acid derived
oxylipins formed via
cyclooxygenases and
lipoxygenases were higher in females, while
oxylipins from other
fatty acids and via
cytochrome P450 enzymes were higher in males. The consistent and unique patterns of
oxylipin alterations in the different models indicates the importance of these bioactive
lipids in
cystic renal diseases, suggesting that pharmacological agents (e.g.
cyclooxygenase inhibitors) may be useful in treating these disorders, for which effective treatment remains elusive.