396-P: Consequences of Knockout of the Histone Demethylase KDM6B from Myeloid Cells Are Context-Dependent in Diabetic Kidney Disease

Introduction & Objective: Epigenetic processes and inflammation have each emerged as key players in the development of diabetic kidney disease. Here, we compared the consequences of knockout of the epigenetic enzyme and histone demethylase, KDM6B from myeloid cells in diabetic mice and mice with obstructive uropathy.

Methods: Myeloid cell KDM6B knockout (KDM6B^MyeloidKO) mice were generated by breeding Kdm6b^fl/fl mice with LysMCre⁺mice and compared to LysMCre⁺ controls (KDM6B^Ctrl). M-CSF levels were measured by cytokine array of media conditioned by bone marrow-derived macrophages (BMDMs). Mice were studied either 12 weeks after diabetes induction with streptozotocin (STZ) or 1 week after unilateral ureteral obstruction (UUO) surgery. Kidney injury and inflammation were assessed by qRT-PCR.

Results: Basal M-CSF secretion was reduced in KDM6B^MyeloidKO BMDMs in comparison to KDM6B^Ctrl BMDMs (KDM6B^Ctrl 62pg/mL, KDM6B^MyeloidKO 4pg/mL, p<0.01), suggestive of a shift towards M1-like polarization. Kidney injury (as assessed by Havcr1 mRNA) was increased ~90-fold in STZ-diabetic mice and ~615-fold in UUO mice. Similarly, kidney inflammation (as assessed by Ccl2 mRNA) was increased ~9-fold in STZ-diabetic mice and ~72-fold in UUO mice. Blood glucose levels were equally elevated in STZ-diabetic KDM6B^Ctrl and KDM6B^MyeloidKO mice. Knockout of KDM6B from myeloid cells attenuated Havcr1 and Ccl2 upregulation in UUO mice but not in STZ-diabetic mice.

Conclusion: Kidney inflammation in STZ-diabetic mice is typically mild, and myeloid cell involvement is primarily through M1-like responses that are independent of the histone demethylase KDM6B. In contrast, myeloid KDM6B contributes to the more advanced inflammation and injury associated with obstructive uropathy. These findings underscore the importance of the physiological context in determining the actions of ostensibly ‘epigenetic enzymes’ in kidney disease, including that caused by diabetes.