Figure 1: The pathophysiology of DN

The pathophysiology of DN involves several mechanisms, as hyperglycemia caused by diabetes triggers various harmful processes within the kidneys. These processes can be generally categorized into hemodynamic, metabolic, inflammatory, and oxidative stress, which are the primary contributors to the disease's development. This added glucose burden, along with increased oxidative stress, triggers a detrimental cascade that leads to tubular fibrosis and the development of DN. Abbreviations: VEGF, Vascular Endothelial Growth Factor; TGF-B, Transforming Growth Factor Beta; IGF-1, Insulin-like Growth Factor-1; RAAS, Renin-Angiotensin-Aldosterone System; PG, Prostaglandins; SGLT2, Sodium/Glucose Cotransporter 2; GFR, Glomerular Filtration Rate; TNF-a, Tumor Necrosis Factor alpha; SAA, serum amyloid A; IL-1B, Interleukin-1 beta; ROS, Reactive Oxygen Species; NOX, NADPH Oxidase; AGEs, advanced glycation end products; JAK-STAT, Janus kinase/ Signal Transducers and Activators of Transcription; MCP-1, monocyte chemoattractant protein 1; MAPK, mitogen-activated protein kinase; SMAD 2/3, suppressor of mothers against decapentaplegic 2/3; NF-kB, nuclear factor kappa B; ECM, extracellular matrix.

Figure 2: GLUT1 and AKR1B1 Pathway involved in the development of DN

Elevated blood sugar levels trigger the polyol pathway, producing glutathione, which decreases when NADPH levels fall. This leads to osmotic stress and oxidative stress, causing DN. Fructose produced through the polyol pathway is phosphorylated, producing fructose-3-phosphate, which is converted into 3-deoxyglucosone and methylglyoxal, which create AGEs. The DAG-PKC pathway controls vascular function, controlling endothelial permeability, vasoconstriction, extracellular matrix synthesis, cell proliferation, angiogenesis, cytokine activation, and leukocyte adhesion. Activation of DAG-PKC disrupts glomerular blood flow, causing albuminuria and promoting extracellular matrix accumulation. GLUT1 transports glucose in mesangial cells, stimulating signaling pathways that promote glomerulosclerosis. Synthesis of Ang II and TGF-β enhances GLUT1 gene expression, increasing glucose flow and contributing to glomerulosclerosis. Abbreviations: AGES - RAGE, Advanced Glycation End products - Receptor of Advanced Glycation End products; AKR1B1, Aldo-Keto Reductase Family 1 Member B; ANGII, Angiotensin II; ATR, Angiotensin II Receptors; CTGF, Connective Tissue Growth Factor; DAG, Diacylglycerol; DAG-PKC, Diacylglycerol-Protein Kinase C; DHAP, Dihydroxyacetone Phosphate; GA3P, Glyceraldehyde 3-Phosphate; GLUT 1, Glucose Transporter 1; GR, Glutathione Reductase; GSH, Reduced Glutathione GSSG, oxidized glutathione; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NF-KB, Nuclear Factor Kappa B B. NO, Nitric oxide; ROS, Reactive Oxygen Species; SDH, Sorbitol dehydrogenase; TGF-B, Transforming Growth Factor Beta; VEGF, Vascular Endothelial Growth Factor.

Figure 3: RAGE Pathway involved in the development of DN

Sustained hyperglycemia increases the production of AGEs that stimulate RAGEs, leading to tubule-interstitial fibrosis, inflammation, and glomerulosclerosis. The interaction between RAGE and AGEs triggers oxidative stress, chronic inflammation, and activation of signaling pathways in renal tissues, contributing to the development of glomerulosclerosis (DN). NF-κB promotes the transcription of genes for pro-inflammatory cytokines and adhesion molecules, while AGEs activate Akt in renal cells, resulting in enhanced permeability of podocytes and impaired endothelial homeostasis. Jak/Stat proteins encourage heightened inflammation and cell multiplication, resulting in kidney injury. An intensified triad of oxidative stress, inflammation, and fibrosis leads to DN, with increased activities of NADPH and ROS levels, reduced antioxidant enzyme activities, and elevated proinflammatory cytokines like TNF-α and IL-6. The increased production of profibrotic cytokines, TGF-β, and extracellular fibrotic fibers, fibronectin, and collagen, contributes to the development of DN. Abbreviations: AGEs, Advanced Glycation End products; Ang II, Angiotensin II; Cox-2, Cyclooxygenase 2; CTGF, Connective Tissue Growth Factor; eNOS, Endothelial Nitric Oxide Synthase; ICAM-1, Intercellular Adhesion Molecule 1; IL-6, Interleukin 6; IL-8, Interleukin 8; iNOS, Inducible Nitric Oxide Synthase; JAK/STAT, Janus Kinase/Signal Transducers and Activators of Transcription; LOX, Lysyl Oxidase; MAPK, Mitogen-Activated Protein Kinase; MMP, Matrix Metalloproteinases; NF-KB, Nuclear Factor Kappa B. NO, Nitric Oxide; NOX, NADPH Oxidase; PI3K-AKT, Phosphatidyl Inositol 3-Kinase-protein kinase B; RAGE, Receptor of Advanced Glycation End product; ROS, Reactive Oxygen Species; TGF-B, Transforming Growth Factor Beta; TNF-α, Tumor Necrosis Factor Alpha; VCAM-1, Vascular Cell Adhesion Molecule 1; VEGF, Vascular Endothelial Growth Factor.