A High-Fat Diet Increases Kidney Fibrosis Through Regulating TGF-β and PDGF-β Signaling Pathways in Normotensive and...

Hypertension and obesity are well-established risk factors for chronic kidney disease (CKD). This study investigates the interaction between these two factors in CKD using animal models. Twelve-week-old normotensive Wistar Kyoto (WKY), spontaneously hypertensive (SHR), and stroke-prone spontaneously hypertensive (SHR-SP) rats were fed either a normal diet (control) or a high-fat diet (HFD) for eight weeks. Kidney pathology and molecular mechanisms were assessed via immunostaining, real-time PCR, and Western blotting. In the control-fed groups, SHR-SP showed the most severe glomerular and tubular fibrosis, followed by SHR. The HFD exacerbated fibrosis in both the WKY and SHR rats but not in the SHR-SP rats. The levels of the mesangial marker smooth muscle α-actin (SMA) in the glomeruli were highest in the control-fed SHR-SP rats. HFD feeding increased glomerular SMA levels in WKY and SHR but not in SHR-SP. The levels of the mesenchymal marker vimentin were elevated in the control-fed SHR-SP rats compared to the other control-fed animals. The HFD increased the vimentin levels in WKY but decreased them in SHR-SP. The HFD increased senescence and inflammatory markers in the kidneys of the WKY and SHR rats. The HFD-fed WKY and SHR rats also showed upregulation of platelet-derived growth factor β (PDGFβ) signaling molecules. Among the control-fed animals, the transforming growth factor β (TGFβ) and TGFβ receptor 2 (TGFβR2) levels were elevated in SHR-SP. HFD feeding increased the TGFβR2 levels in WKY and the SHR and TGFβ levels in WKY. Similarly, SMAD2/3 activation was the highest in the SHR-SP control group. HFD feeding increased the SMAD2/3 activation in the kidneys of the WKY and SHR rats. Thus, our findings demonstrate that a high-fat diet can intensify renal fibrosis independent of hypertension through TGFβ and PDGFβ signaling within a two-month timeframe.