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Innovative Medicines & Omics Current approach in the management of kidney disease

induced phosphorylation of SMAD2/3 in human kidney-2 investigations are necessary to demonstrate whether
(HK-2) cells. By modifying TGF-β1/SMADd3 and STAT3 fisetin’s beneficial and senolytic properties can be
signaling, fisetin helps to improve kidney fibrosis. 56,57 translated into human use. According to a recent cohort
Fisetin also reduces the release of inflammatory cytokines, study sub-analysis, serum levels of senescence-associated
AGEs, ROS, and NLR family pyrin domain containing 3 secretory phenotype factors, MMP-3 and MMP-9, platelet-
(NLRP3) inflammasome – factors associated with diabetic derived growth factor AA, IL-6 and IL-8, monocyte
nephropathy. When the NLRP3 inflammasome is activated chemoattractant protein-1 (MCP-1), and growth
in mice, podocyte proteins such as nephrin and podocin differentiation factor 11 and 15, dropped between baseline
are lost, accompanied by mitochondrial dysfunction. and follow-up visit in healthy individuals who self-dosed
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Tubular injury in animals has been linked to increased high with 100 mg/day of fisetin. (Figure 2).
glucose-induced EMT and the involvement of SMAD3,
p38 MAPK, extracellular signal-regulated kinase 1 (ERK1), 3.7.3. Kaempferol
and ERK2 signaling pathways. Fisetin treatment reduced Kaempferol, a flavonoid widely distributed in vegetables
the expression of fibronectin, collagen, and vascular and fruits, including broccoli, tea, and grapes, exhibits
endothelial growth factor A (VEGFA) while increasing antioxidant and anti-inflammatory properties. In
matrix metalloproteinases 2/9. This was primarily caused HK-2 cells, lipopolysaccharide (LPS) upregulated the
by inactivating the TGF-β/SMAD2/3 pathways, which production of TNF-α and IL-1β, demonstrating its ability
inhibits the production of ECM in the kidney. Both to induce inflammation. However, the administration
in vitro and in vivo experiments demonstrated that fisetin of kaempferol considerably decreased the LPS-induced
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effectively protects against kidney fibrosis. Fisetin shows apoptosis in HK-2 cells. LPS also induced STAT3 and
significant potential as a senolytic medication with a NF-κB, which subsequently increased procalcitonin
variety of therapeutic applications, although human data expression, a validated blood biomarker in septic patients.
remain limited currently. Carefully supervised clinical Kaempferol played a crucial anti-inflammatory role in

Figure 2. Mechanism of action of fisetin in the protection of diabetic nephropathy
Abbreviations: VEGFA: Vascular endothelial growth factor A; ROS: Reactive oxygen species; NLRP3: NLR family pyrin domain containing 3; AGE: Advanced
glycation end-product; MAPK: Mitogen-activated protein kinases; TGF-β1: Transforming growth factor-β1; EMT: Epithelial-to-mesenchymal transition;
ECM: Extracellular matrix.

Volume 2 Issue 1 (2025) 43 doi: 10.36922/imo.4969