High expression of angiotensin-converting enzyme in macrophages exacerbates renal interstitial damage in diabetic mice.

Angiotensin-converting enzyme (ACE), primarily expressed in vascular endothelial and renal tubular epithelial cells, regulates vascular tone and contributes to kidney injury, including in diabetic kidney disease (DKD). While tubular ACE deletion ameliorates tubulointerstitial injury in diabetic mice, the role of ACE in macrophages remains unclear. We investigated diabetic ACE 10/10 mice, which overexpress ACE exclusively in myelomonocytic cells and lack ACE in other tissues, including the kidney. In diabetic ACE 10/10 mice, the absence of endothelial ACE resulted in the elimination of glomerular hyperfiltration with preservation of podocyte structure. However, albuminuria levels remained comparable to those in diabetic WT mice. Furthermore, despite the lack of tubular ACE, which is recognized as a contributor to tubulointerstitial fibrosis, the extent of fibrosis was similarly unchanged. Flow cytometry revealed that ACE expression in kidney-resident macrophages increased approximately threefold in both diabetic WT and ACE 10/10 mice, but not in peritoneal macrophages. In vitro, ACE-overexpressing macrophages showed increased interleukin-6 production and enhanced chemotaxis upon lipopolysaccharide stimulation. These findings suggest that ACE expressed in kidney-resident macrophages contributes to proximal tubular albuminuria and tubulointerstitial fibrosis in DKD, independently of glomerular hyperfiltration and tubular ACE. Although macrophage ACE represents a minor fraction of total renal ACE, it may serve as a novel therapeutic target.