Abstract
Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD). Existing treatments cannot control the progression of diabetic nephropathy very well. In diabetic nephropathy, Many monocytes and macrophages infiltrate kidney tissue. However, the role of these cells in the pathogenesis of diabetic nephropathy has not been fully elucidated. In this study, we analyzed patient kidney biopsy specimens, diabetic nephropathy model animals. Meanwhile, we cocultured cells and found that in diabetic nephropathy, damaged intrinsic renal cells (glomerular mesangial cells and renal tubular epithelial cells) recruited monocytes/macrophages to the area of tissue damage to defend against and clear cell damage. This process often involved the activation of different types of macrophages. Interestingly, the infiltrating macrophages were mainly M1 (CD68+iNOS+) macrophages. In diabetic nephropathy, crosstalk between the Notch pathway and NF-κB signaling in macrophages contributed to the polarization of macrophages. Hyperpolarized macrophages secreted large amounts of inflammatory cytokines and exacerbated the inflammatory response, extracellular matrix secretion, fibrosis, and necroptosis of intrinsic kidney cells. Additionally, macrophage depletion therapy with clodronate liposomes and inhibition of the Notch pathway in macrophages alleviated the pathological changes in kidney cells. This study provides new information regarding diabetic nephropathy-related renal inflammation, the causes of macrophage polarization, and therapeutic targets for diabetic nephropathy.
Highlights
Diabetes has become a global public health problem because of its increasing prevalence
We evaluated kidney biopsy specimens from the patients and used kidney tissues from patients undergoing nephrectomy due to trauma as normal controls
The number of infiltrating macrophages in the kidney and degree of renal macrophage infiltration positively correlate with the level of proteinuria, a decline in renal function in 5 years and disease prognosis [7–9]
Summary
Diabetes has become a global public health problem because of its increasing prevalence. According to the latest statistics from the International Diabetes Federation (IDF), in 2019, approximately 10% of people worldwide had diabetes, with the disease affecting approximately 463 million adults (aged 20-79 years) [1]. According to the United States Renal Data System (USRDS) Annual Data Report, diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) [4]. The pathogenesis of diabetic nephropathy is complicated and has not been fully elucidated. According to the traditional view, the pathogenesis of diabetic nephropathy involves genetic factors, hemodynamic effects, serum glucose level and/or lipid metabolism disorders [3, 5]. The role of macrophages (mjs) in the pathogenesis of diabetic nephropathy has attracted increasing attention. In DKD, numerous monocytes/macrophages accumulate in the glomerulus and renal interstitium. Infiltration by various inflammatory cells and the massive release of inflammatory factors may play an important role in the development of DKD. Several studies have confirmed a large number of infiltrating macrophages in the diabetic kidney, and the number of infiltrating macrophages positively correlates with multiple pathological changes in inherent kidney cells in diabetic nephropathy [6–10]
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