Roles of pattern recognition receptors in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.

Keywords: Diabetic nephropathy; Innate immunity; Pattern recognition receptor; Pathogenesis.

Fig. 1

Pathogenic mechanisms of CRP causing inflammation and renal fibrosis in diabetic nephropathy CRP binds to FcγRII and activates the NF-κB signal pathway to induce inflammation. CRP can also activate the ERK1/2, Wnt/β-catenin, TGF-β1/Smad3, and non-TGF-β1/Smad3 signaling pathways to induce renal fibrosis. CRP, C-reactive protein; FcγRII, type II Fc receptor for immunoglobulin G (IgG); NF-κB, nuclear factor-κB; ERK, extracellular signal-regulated kinase; TGF-β1, transforming growth factor-β1; MAP, mannose-binding lectin (MBL)-associated protein; mTOR, mammalian target of rapamycin; EMT, epithelial-mesenchymal transformation

Fig. 2

TLR signaling pathways in diabetic nephropathy When activated by DAMPs (such as HMGB1, HSP, and AGEs), TLR2 and TLR4 directly activate MyD88 via TIRAP, TLR5, TLR7, TLR9, and TLR11, and finally activate NF-κB, IRF7, and AP-1/ATF-2. In addition, TLR4 can directly activate TRIF via TRAM and TLR3, which ultimately leads to the activation of IRF3 and IRAK4. Activation of NF-κB and AP-1/ATF-2 can induce the production of inflammatory factors, while activation of IRF3 and IRF7 can induce the production of type 1 IFNs, which together lead to the occurrence of DN. TLR, Toll-like receptor; DAMP, danger-associated molecular pattern; HMGB1, high-mobility group protein box 1; HSP, heat shock protein; AGEs, advanced glycation end products; MyD88, myeloid differentiation factor 88; TIRAP, Toll/interleukin-1 (IL-1) receptor domain-containing adaptor protein; NF-κB, nuclear factor-κB; IRF, interferon (IFN) regulatory factor; AP-1, activator protein 1; ATF-2, activating transcription factor-2; TRIF, Toll/IL-1-resistance domain-containing adaptor inducing IFN-β; TRAM, TRIF-related adaptor molecule; IRAK4, IL-1 receptor-associated kinase 4; DN, diabetic nephropathy; TRAF, tumor necrosis factor (TNF) receptor-associated factor; TAK1, transforming growth factor β-activated kinase-1; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; TRAK, trafficking kinesin protein; OPN, osteopontin; TRK, tropomyosin-related kinase

Fig. 3

NLR signaling pathways in diabetic nephropathy The NLRP3 inflammasome can be activated by the ROS/TXNIP/NADPH oxidase signaling pathway and extracellular ATP, and inhibited by IL-22. Activated NLRP3 can cause excessive amounts of inflammatory cytokines such as IL-1β and IL-18. NOD1/2 can activate MAPKs and NF-κB, and NLRC4 and NLRC5 can also activate NF-κB. In addition, NLPC4 and NLRC5 affect the JNK and TGF-β/Smad pathways, respectively. NLR, nucleotide-binding oligomerization domain (NOD)-like receptor; NLRP3, NLR protein 3; ROS, reactive oxygen species; TXNIP, thioredoxin-interacting protein; NADPH, nicotinamide adenine dinucleotide phosphate; ATP, adenosine triphosphate; IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; NLRC, NLR family caspase recruitment domain (CARD)-containing protein; JNK, c-Jun N-terminal kinase; TGF, transforming growth factor; RICK, receptor interacting protein kinase (RIP)-like-interacting caspase-like apoptosis-regulatory protein (CLARP) kinase; DN, diabetic nephropathy