NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation

Abstract

NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/ db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5) and wild-type (WT) diabetic mice. We found that Nlrc5 mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5 mice, associated with NF-κB pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-κB and TGF-β/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-κB and TGF-β/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.-Luan, P., Zhuang, J., Zou, J., Li, H., Shuai, P., Xu, X., Zhao, Y., Kou, W., Ji, S., Peng, A., Xu, Y., Su, Q., Jian, W., Peng, W. NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.

NLRC5: potential novel non-invasive biomarker for predicting and reflecting the progression of IgA nephritis

“…IgAN appears to be a systemic disease, with the kidney is an important target organ for immune complex deposits, and we found NLRC5 in IgAN like C1q complement in lupus nephritis. We assume that low expression of serum NLRC5 may contribute little to the deposition of NLRC5 in the kidneys but may serve as a trigger for inflammatory reaction in IgAN, local production of NLRC5 by endothelial cells, dendritic cells, and macrophages in the kidneys might be the main source of local NLRC5 deposition because of the local inflammatory response in IgAN, as NLRC5 promotes proinflammatory responses in parenchymal cells in acute renal failure (AKI) [ 16 ] and in mesangial cells in diabetic nephropathy (DN) [ 34 ], beyond the regulation of MHC class I genes. Therefore, we think that the lack of a correlation between the expression of NLRC5 in serum and tissue may be caused by the complex and diverse role of NLRC5 in different cells in IgAN.…”

“…found that gene silencing of NLRC5 decreased hypoxia-induced production of proinflammatory mediators and apoptosis in proximal tubule epithelial cells. Luan et al [ 34 ]. found that NLRC5 promotes inflammation and fibrosis partly through effects on NF-kB and TGF-β/Smad pathways during DN progression.…”

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

“…147 Knockout of NLRC5 also protects against development of kidney injury in diabetic mice by inhibiting macrophage infiltration, proinflammatory cytokine expression, and collagen IV deposition as well as increasing podocin and nephrin levels. 56…”

Network Pharmacology-based Prediction of Mechanism of Shenzhuo Formula for Application to DN

“…Similarly, the results of KEGG enrichment analysis showed that shenzhuo formula takes an effect in the treatment of DN through multiple pathways. Through further research, we found that these pathways have been experimentally confirmed, such as TNF signaling pathway [35], HIF-1 signaling pathway [36], Toll-like receptor signaling pathway [37], FoxO signaling pathway [38], Focal adhesion [39], NOD-like receptor signaling pathway [40] and other ways to exert anti-DN potential. These results were also consistent with the result predicted by the network analysis.…”