Abstract
Renal inflammation is a hallmark of diabetic kidney disease. Endothelin-1 (ET-1), a potent vasoactive peptide that acts through two receptors (ET A and ET B ), has been implicated in diabetes and is upregulated in patients with diabetic nephropathy (DN) and in animal models of diabetic kidney injury. ET B receptors are highly expressed in renal outer medulla (OM). ET-1 exerts pro-inflammatory actions in the kidney; however, the mechanisms by which ET-1 mediate these effects are unclear. The present studies were designed to determine the role of the ET B receptor in priming inflammasome signaling pathways, as well as its role in the activation of dendritic cells (DCs), in the renal OM during type 1 diabetes. Diabetes was induced in ET B deficient (ET B def) and transgenic (TG) control rats by i.v. injection of streptozotocin (STZ). 10 wk later, 24-h urine and kidneys were collected for analysis of kidney damage. Diabetic ET B def rats presented exaggerated kidney damage compared to diabetic TG controls, with greater excretion of protein, albumin and ET-1, cortical expression of KIM-1 (respectively: 90±12 vs. 45±6 mg/day, 41±8 vs. 12±4 mg/day, 18±1 vs. 15±1 pg/day, 12±1 vs. 7±1 pg/mg prot; n=4- 6/group, p<0.05), and excessive kidney fibrosis, tubular dilation and cell death. Immunohistochemistry for the DC activation marker CD83 also demonstrated exaggerated activation of DCs in renal OM of diabetic ET B def rats. Expression of inflammasome genes in renal OM was assessed by RT-PCR array. Diabetes led to upregulation of NLRP5 (4-fold increase vs. TG controls; n=3/group; p<0.05) and IL-1β (~3-fold increase vs. TG controls; n=3/group; p<0.05) in OM of ET B def rats. In addition, PSTPIP1, a negative regulator of the inflammasome, was decreased in OM of diabetic ET B def rats vs. TG controls. Together, these results demonstrate that dysfunction of the ET B receptor leads to worsening of diabetic kidney injury and overactivation of the inflammasome and DCs specifically in the renal OM. These results highlight the protective role of ET B receptors against the development of diabetes- induced kidney inflammation and damage. Funded by NIH T32 DK007545 to CDM and P01 HL69999, P01HL136267, AHA SFRN 24450002 and U01HL117684 to DMP and JSP.
Published Version
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