Molecular Mechanisms and Clinical Evidence Supporting the Four Pillars of Therapy in Diabetic Kidney Disease: Emerging Therapeutic Perspectives

Figures

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  Figure 1. The histological and molecular characteristics of DKD. Blue arrows indicate effects, black horizontal arrows indicate the flow of substance, and red upward and downward arrows indicate an increase and a decrease of activity or substances, respectively. AT1R, angiotensin II type 1 receptor; ECM, extracellular matrix; ENaC, epithelial sodium channel; Epo, erythropoietin; G, glucose; GBM, glomerular basement membrane; MR, mineralocorticoid receptor; NHE3, Na+/H+ exchanger 3; ROS, reactive oxygen species; SGLT2, sodium-glucose cotransporter 2; TGF, tubuloglomerular feedback.

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  Figure 2. The mechanisms of possible renal protective effects of SGLT2is. Blue arrows indicate effects, black horizontal arrows indicate the flow of substance, and red upward and downward arrows indicate an increase or decrease in activity or substances, respectively. ATP-binding cassette, subfamily G, 2 (ABCG2); ECM, extracellular matrix; Epo, erythropoietin; ER, endoplasmic reticulum; G, glucose; GLUT9, glucose transporter 9; ROS, reactive oxygen species; SGLT2, sodium-glucose cotransporter 2; SGLT2is, sodium-glucose cotransporter 2 inhibitors; TGF, tubuloglomerular feedback; UA, uric acid; URAT1, urate transporter 1.

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  Figure 3. The mechanisms of possible renal protective effects of GLP-1RAs. Blue arrows indicate effects, black horizontal arrows indicate the flow of substance, and red upward and downward arrows indicate an increase or decrease in activity and substances, respectively. ENaC, epithelial sodium channel; GLP-1R, glucagon-like peptide-1 receptor; GLP-1RAs; glucagon-like peptide-1 receptor agonists; NHE3, Na+/H+ exchanger 3; PI3K-Akt, phosphatidylinositol 3′-kinase-Akt; ROS, reactive oxygen species; TGF, tubuloglomerular feedback.

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  Figure 4. The inhibitory effects of febuxostat and dotinurad on molecules associated with uric acid and uremic toxin indoxyl sulfate metabolism. Black arrows indicate the flow of substance and blue arrows indicate inhibitory effects of febuxostat and dotinurad on molecules associated with uric acid and indoxyl sulfate metabolism. ATP-binding cassette, subfamily G, 2 (ABCG2); IS, indoxyl sulfate; UA, uric acid; URAT1, urate transporter 1; XO, xanthine oxidase.

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  Figure 5. Differential effects of metformin and imeglimin on mitochondria, with resulting differential renal protective effects and risk of lactic acidosis. Black arrows indicate effects and red upward arrows indicate an increase in activity. AMPK, AMP-activated protein kinase; GSIS, glucose-stimulated insulin secretion; mGPDH, mitochondrial glycerol-3-phosphate dehydrogenase; NAMPT, nicotinamide phosphoribosyltransferase.

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  Figure 6. Effects of fenofibrate and pemefibrate on lipid, uric acid, and indoxyl sulfate metabolism. Black horizontal arrows indicate the flow of substance and effects and red upward and downward arrows indicate an increase or decrease in activity or substances, respectively. The red dotted arrows indicate activating effects and the blue dotted arrows indicate inhibitory effects. ATP-binding cassette, subfamily G, 2 (ABCG2); HDL, high-density lipoprotein; IS, indoxyl sulfate; LPL, lipoprotein lipase; PPARα, peroxisome proliferator-activated receptor alpha; TG, triglyceride; UA, uric acid; URAT1, urate transporter 1; VLDL, very-low-density lipoprotein; XO, xanthine oxidase.

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  Figure 7. Four pillars and the emerging drugs for DKD. Grey bold arrows indicate pathological associations among metabolic disorders, RAS and MR activation, and DKD. Pink arrows indicate improvement and a dotted blue arrow indicates possible additional beneficial effects of the emerging drugs on DKD. GLP-1RAs, glucagon-like peptide-1 receptor agonists; nsMRAs, non-steroidal mineralocorticoid receptor antagonists; RASis, renin-angiotensin system inhibitors; SGLT2is, sodium-glucose cotransporter 2 inhibitors.