Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of diabetic kidney disease (DKD)

Figures

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  Fig. 1. The three PPAR subtypes exhibit a compartment-specific distribution in the kidney and function synergistically to exert protective effects. PPARα, enriched in proximal tubules, promotes FAO and suppresses inflammation and fibrosis. PPARγ, located in collecting ducts and glomerular cells, attenuates fibrosis, restores mitochondrial function, and enhances antioxidant defense. PPARβ/δ, widely expressed throughout the kidney, confers protection by reducing albuminuria and inflammation. PPAR peroxisome proliferator-activated receptor, PPARγ peroxisome proliferator-activated receptor gamma, PPARα peroxisome proliferator-activated receptor α, PPARβ peroxisome proliferator-activated receptor β, FAO Fatty acid oxidation; (Created by Biorender.com).

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  Fig. 2. PPARs play a central role in regulating podocyte homeostasis. Protective Pathways (Right): NCOA3 suppresses the transcription of Fyn in a PPARγ-dependent manner, thereby promoting podocyte autophagy. PPARγ enhances antioxidant capacity through the Klotho-Forkhead Transcription Factor O1 (FoxO1) axis; meanwhile, PEDF and Perilipin 2 exert anti-apoptotic effects via PPARγ. As a key molecule downstream of AdipoRs, PPARα maintains metabolic homeostasis through the AMPK pathway. Damaging Pathways (Left): miR-27a activates β-catenin via PPARγ, inducing EMT and podocyte apoptosis. Additionally, Trim63 mediates the ubiquitination of PPARα, resulting in FAO deficiency and mitochondrial dysfunction. PPARs Peroxisome proliferator-activated receptors, PPARγ peroxisome proliferator-activated receptor gamma, PPARα peroxisome proliferator-activated receptor α, SOD2 superoxide dismutase 2, NCOA3 nuclear receptor coactivator 3, PEDF pigment epithelium-derived factor, LKB1 liver kinase B1, AMPK adenosine monophosphate-activated protein kinase, EMT epithelial-mesenchymal transition, FAO fatty acid oxidation, AdipoRs adiponectin receptors; (Created by Biorender.com).

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  Fig. 3. In DKD, PPARγ integrates key pathological signals in mesangial cells and directly regulates clinically relevant renal injury. PPARγ mediates anti-inflammatory effects by inhibiting the AGE-RAGE pathway and NF-κB pathway. Moreover, PPARγ exerts antifibrotic effects by antagonizing TGF-β signaling and downregulating Collagen I, Collagen IV, PAI-1, and fibronectin. Furthermore, PPARγ alleviates lipid accumulation through the LXRα-ABCA1 axis. The activity of PPARγ is controlled by epigenetic factors such as miR-27a and lncRNA TUG1. PPARγ agonists (e.g., rosiglitazone, troglitazone) orchestrate the aforementioned pathways to collectively exert renoprotective effects and delay the functional decline of DKD. PPARγ peroxisome proliferator-activated receptor gamma, DKD diabetic kidney disease, Collagen IV type IV collagen, Collagen I type I collagen, TGF-β Transforming growth factor-β, 15d-PGJ2 15-deoxy-Δ12,14-prostaglandin J2, PAI-1 plasminogen activator inhibitor-1, MCP-1 monocyte chemoattractant protein-1, RANTES Regulated upon activation, normal T-cell expressed and secreted, AGE advanced glycation end product, RAGE receptor for advanced glycation end product, LXRα liver X receptor α,…

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  Fig. 4. In the renal tubules of DKD, PPARs function as a signaling hub to orchestrate metabolic, fibrotic, and inflammatory responses. PPARα enhances FAO by activating AMPK and upregulating CPT1b, thereby alleviating lipotoxicity. On the other hand, PPARγ inhibits EMT and suppresses TECs by upregulating the Apoh/UCP2 axis; PPARγ also antagonizes NF-κB and STAT-1 to mitigate inflammation. Conversely, the HG environment upregulates the fatty acid translocase CD36 via the AKT-PPARγ axis, resulting in lipid deposition and inducing lipotoxic injury in renal tubules. PPARγ peroxisome proliferator-activated receptor gamma, PPARα peroxisome proliferator-activated receptor α, TECs tubular epithelial cells, UCP2 uncoupling protein 2, KLF6 Krüppel-like factor 6, ANXA1 Annexin A1, CPT1b carnitine palmitoyltransferase 1b, DQ dasatinib and quercetin, NF-κB nuclear factor-kappa B, EMT epithelial-mesenchymal transition, FAO fatty acid oxidation, ATP adenosine triphosphate, pACC phosphorylated Acetyl-CoA Carboxylase, AMPK adenosine monophosphate-activated protein kinase, α-SMA alpha-smooth muscle actin, Collagen I type I collagen, HG high glucose, STAT-1 signal transducer and activator of transcription…