Table 2.

Studies Evaluating Inflammation in the Renal System

Pre-Clinical Studies
Reference	Model	Treatment	Primary Finding	Inflammatory Measures	Additional Findings
Hasan R et al. [37]	Long Evans rats exposed to isoprenaline to induce renal oxidative damage	Canagliflozin for 2 weeks	↑Antioxidant/anti-inflammatory signaling pathways	↓Inflammatory cell infiltration ↑AMPK ↑Akt ↑eNOS ↓iNOS ↓NOX4 ↓Caspase 3	↓Apoptosis ↓Renal fibrosis
Vallon V et al. [38]	Type 1 diabetic Akita mice	Empagliflozin for 15 weeks	↓Renal hyperfiltration	↓CCL2 ↓CD14 ↓IL-6 ↓TIMP2	↓NF-κB ↓Albuminuria ↓Kidney growth makers ↔NOX2, NOX4, CCL5, TGFβ, renal collagen
Terami N et al. [39]	Diabetic db/db mice and cultured tubular epithelial cells (mProx24)	Dapagliflozin for 12 weeks in vivo and incubation with dapagliflozin in vitro	↓Progression of diabetic nephropathy	↓Macrophage infiltration (CD14, CD11c, CD206) ↓Mcp1, Tgfb expression ↓ROS	↓β-cell damage ↓Albuminuria ↓Renal fibrosis
Birnbaum Y et al. [40]	BTBR ob/ob or wild-type mice	Dapagliflozin, vehicle, or dapagliflozin + saxagliptin for 8 weeks	↓BUN	↓NLRP3 inflammasome activation ↓Tnfa, Il1b, Il6 expression	↓AMPK phosphorylation
Zaibi N et al. [41]	Human proximal tubular cells (HK-2)	Dapagliflozin for 24 hours in vitro	↓Oxidative stress	↓ROS	↓Apoptosis Modified calcium dynamics
Das NA et al. [42]	Human proximal tubular cells (HK-2)	Empagliflozin for 24 hours in vitro	↓Epithelial to mesenchymal transition ↓Epithelial cell migration	↓ROS ↓NF-κB activation	↓p38 MAPK ↓miR-21 ↓MMP2
Ishibashi Y et al. [43]	Primary cultured human proximal tubular cells from normal kidney	Tofogliflozin for 24 hours in vitro	↓Oxidative stress ↓Profibrotic factors	↓ROS ↓MCP-1	↓Apoptosis
Yao D et al. [44]	Human proximal tubular cells (HK-2)	Dapagliflozin for 48 hours in vitro	↓HMGB1-RAGE-NF-κB signaling pathway	↓ROS ↓MCP-1 ↓NF-κB activation	↓Fibrosis makers (FN and Col 1) ↓ICAM-1
Satou R et al. [46]	Mouse proximal tubular cells cultured in high glucose conditions	Canagliflozin in vitro	↓Angiotensinogen	↓ROS
Woods TC et al. [47]	New Zealand obese mice on high fat diet to induce diabetes	Canagliflozin for 6 weeks	↓Angiotensinogen ↓Tubular fibrosis	↓ROS ↓Monocyte/macrophage infiltration	Normalization of systolic BP
Ke Q et al. [48]	Mouse C57BL/6 with kidney fibrosis induced by ischemic/reperfusion injury and primary proximal tubular epithelial cells	Dapagliflozin for 1 week in vivo and incubation with dapagliflozin in vitro	↓Renal fibrosis ↑Itaconate (metabolic from TCA cycle)	↓NLRP3 inflammasome activation ↓Caspase 1 ↓IL-1β ↓IL-18	↓mTOR signaling ↓HIF-1α signaling
Pirklbauer M et al. [49]	Human proximal tubular cells (HK-2 and RPTEC/TERT1) treated with TGF-β	Empagliflozin or canagliflozin in vitro	↓Mediators of renal fibrosis	ND	↓Tenascin C (TNC) ↓Thrombospondin 1(THBS1) ↓Platelet derived growth factor subunit B (PDGF-B)