Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

Abstract

Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

Keywords: diabetic kidney disease; inflammatory mechanism; signaling pathway; therapeutic targets; tubulointerstitium.

Figure 1

Diabetic tubular and interstitial inflammatory states. In DKD patients, in the tubulointerstitium, excessive protein and a high glucose environment lead to an inflammatory state of renal tubular epithelial cells. The generated large amount of pro-inflammatory cytokines attract inflammatory cells, which secrete a significant amount of inflammatory cytokines. The accumulation of inflammatory factors at the site of injury leads to tubular atrophy, interstitial inflammation, and fibrosis. Additionally, the upregulation of surface receptors on renal tubular epithelial cells further amplifies the inflammatory response, contributing to the progression of DKD. PTEC, Renal Tubular Epithelial Cells; IL-R, Interleukin Receptor; TLR2, Toll-like Receptor 2; TLR4, Toll-like Receptor 4; TNF-R, Tumor Necrosis Factor Receptor; IFN-R, Interferon Receptor; RAGE, the Receptor of Advanced Glycation Endproducts; PDGF-R, Platelet-derived Growth Factor Receptor; BMP-R, Bone Morphogenetic Protein Receptor; AT-1R, Angiotensin Receptor 1; TGF-βR, Transforming Growth Factor-β Receptor; MCP-1, Monocyte Chemotactic Protein 1; OPN, Osteopontin; TNF-α, Necrosis Factor-α; G, Glucose; IFN-γ, Interferon γ; TGF-β, Transforming Growth Factor-β; Ang II, Angiotensin II; HMGB1, High-Mobility Group protein B1; ILs, Interleukin; AGEs, Advanced Glycation Endproducts; VCAM-1, Vascular Cell Adhesion Molecule 1; MCs, Mast Cells; By Figdraw (www.figdraw.com).

Figure 2

NF-κB signaling pathway in the pathogenesis of DKD. Activation of NF-κB is tightly regulated by the IκB regulatory protein family. This regulation occurs through the phosphorylation of the inhibitory protein IκB kinase by specific IκB proteins, followed by its degradation via proteolysis. Once freed, NF-κB translocates from the cytoplasm into the nucleus. Within the nucleus, NF-κB binds to specific promoter and enhancer sites on target genes, initiating the process of transcription. This activation leads to increased transcription of genes encoding inflammatory cytokines and other molecules associated with this complication As a result, renal inflammation is triggered due to the involvement of the NF-κB signaling pathway, ultimately contributing to the development of renal inflammation. IL-1R, Interleukin-1 Receptor; DAG, Diacylglycerol; PKC, Protein Kinase C; IkB, NF-kappa-B Inhibitor; FADD, Fas-associated with Death Domain Protein; TRADD, TNF Receptor 1 Associated via the Death Domain; TRAF2, TNF Receptor-Associated Factor 2; RIP, Receptor-interacting Protein; IKKs, IΚB Kinases; TOLLIP, Recombinant Toll Interacting IRAK, Interleukin Receptor-Associated Kinase; ACP, Acyl Carrier Protein; NIK, NF -κB Inducing Kinase; TAK1, Transforming Growth Factor Kinase 1; CTGF; Recombinant Connective Tissue Growth Factor; MyD88, Myeloid Differentiation Factor 88; HSP70, Heatshockprotein70; By Figdraw (www.figdraw.com).

Figure 3

At the core of TGF-β signaling are pro-inflammatory and fibrotic processes. Factors such as albumin, hyperglycemia, and Angiotensinogen II contribute to renal interstitial fibrosis. TGF-β serves as a central mediator in these pro-inflammatory and fibrotic processes. Binding of TGF-β or BMP-7 to their respective receptors results in the formation of heteromeric receptor complexes with activated kinases (ALK5 and ALK3, respectively). This leads to the recruitment and phosphorylation of Smads (Smad2/3 for TGF-β and Smad1/5 for BMP-7). The phosphorylated Smads (pSmad) form heteromeric complexes with Smad4 and translocate to the nucleus, where they regulate gene expression. BMP-7 exerts antagonistic effects on TGF-β signaling, as depicted by its impact on the expression, nuclear shuttling, and phosphorylation of Smad3. Non-Smad signaling pathways of TGF-β can involve the activation of p38 MAPK, JNK, and Rho. Klotho inhibits the binding of TGF-β to cell surface receptors and blocks Wnt signaling, thereby inhibiting the fibrotic process and epithelial-mesenchymal transition (EMT). The specific molecular mechanisms underlying these effects need further investigation and confirmation. TGF-β, Transforming Growth Factor-β; TGF-βR, Transforming Growth Factor-β Receptor; PDGF, Platelet-derived Growth Factor; PDGF-R, Platelet-derived Growth Factor Receptors; BMP-7, Bone Morphogenic Protein-7; BMP-R, Bone Morphogenic Protein Receptor; AGEs, Advanced Glycation Endproducts; RAGE, the Receptor of Advanced Glycation Endproducts; Ang II, Angiotensin II; IFN-γ, Interferon γ; TNF-α, Tumor Necrosis Factor-α; AT-1R, Angiotensin Receptor 1; MAPK, Mitogen-activated Protein; PI3K, Phosphatidylinositol 3 Kinases; PLC-γ, Phospholipase C-γ; NF-kB, Nuclear Factor Kappa-light-chain-enhancer of activated B cells; JAK1, Janus Kinase 1; STAT1, Signal Transducer And Activator Of Transcription 1; PKC, Protein Kinase C; ROS, Reactive Oxygen Species; ERK1/2, Extracellular Signal-regulated Kinase 1/2; PPAR-α, Peroxisome Proliferators-Activated Receptor alpha; Smad, Drosophila Mothers Against Decapentaplegic Protein; CTGF, Connective Tissue Growth Factor; B2KR, Bradykinin 2- Receptor; BK, Bradykinin; EMT, Epithelial-to-Mesenchymal Transition; ECM, Extracellular Matrix; By Figdraw (www.figdraw.com).

Figure 4

Finerenone improves the structure and function of renal tubular epithelial cells. By blocking the mineralocorticoid receptor (MR) and inhibiting the effects induced by the activation of MR by aldosterone, finerenone suppresses the actions of Ang II, PDGF, and EGF. It inhibits the phosphorylation of S6K1 through the ERK1/2 and c-Src/mTOR pathways, reducing oxidative stress and the generation of superoxide anions. Finerenone also increases the bioavailability of nitric oxide, repairs adhesion molecules, and improves the structural damage of proximal tubular cells (PTC). These mechanisms contribute to the maintenance of anti-inflammatory and anti-fibrotic effects in the kidneys. PDGF, Platelet-derived Growth Factor; PDGF-R, Platelet-derived Growth Factor Receptors; Ang II, Angiotensin II; AT-1R, Angiotensin Receptor1; MR, Mineralocorticoid Receptor; ERK1/2, Extracellular Signal-Regulated Kinase 1/2; AP-1, Activator Protein 1; c-Src, Non-receptor Receptor Tyrosine Kinase; EGFR, Epithelial Growth Factor Receptor; mTOR, Mammalian Target of Rapamycin; HIF-1a, Hypoxia-inducible Factor 1 alpha; PTKs, Protein Tyrosine Kinase; PI3K, Phosphatidylinositide 3-Kinases; PIP3, Phosphatidylinositol 3 Phosphate; AKT, Protein Kinase B(PKB); PDK1, 3-Phosphoinositide Dependent Protein Kinase-1; TSC1/2, Tuberous Sclerosis Complex1/2; NOX, NADPH Oxidase; Enos, endothelial Nitric Oxide Synthase; Mn-SOD, Mn-Superoxide Dismutase; TNX, Tenascin-X; EMT, Epithelial-to-Mesenchymal Transition; By Figdraw (www.figdraw.com).