Pre‐transcriptional fibrotic factor alterations do not contribute to high fat diet associated renal fibrosis in Dahl salt sensitive male rats

Abstract

We previously reported that high fat diet (HFD) feeding for 24 weeks promotes hypertension similarly in male and female Dahl salt‐sensitive rats. However, HFD fed males exhibited more severe renal inflammation, fibrosis and injury than females. The underlying mechanisms responsible for sex differences in HFD associated renal fibrosis/injury are not fully understood. It is well established that extracellular matrix (ECM) remodeling is the hallmark of hypertension associated renal fibrosis. Proteins involved in ECM remodeling are key mediators in the fibrogenic process. Therefore, we determined if HFD increases ECM remodeling resulting in renal fibrosis and if sex differences of ECM remodeling in response to HFD contribute to hypertension‐associated renal fibrosis/injury in males. Renal cortex was collected from male and female rats fed a control diet (CD, 10% kcal fat) or a high fat diet (60% kcal fat) for 24 weeks. mRNA expression of fibrosis markers in the renal cortex was assessed, which included transforming growth factor (TGF), smooth muscle actin (SMA), cysteine‐rich angiogenic inducer 61 (CYRG1), connective tissue growth factor (CTGF), collagen (COL1A1, COL3A1, COL1A2), and matrix metalloproteinases (MMP9, MMP14). We found that only MMP9 mRNA levels were significantly elevated in HFD fed females compared to CD fed females. However, MM9 mRNA expression was similar in HFD fed and CD fed males. HFD feeding did not change expression of the other fibrosis markers in males or females. We next determined if elevated MMP9 mRNA levels in HFD females were translated into increased total MMP9 protein and/or increased MMP9 activity. MMP9 activity was determined by zymograph assay. We found that the total MMP9 protein expression and the activity were similar in HFD fed males and females. Our studies suggest that it is unlikely that HFD causes pre‐transcriptional alterations in the fibrosis signaling pathway. HFD associated post‐transcriptional alterations may contribute to renal fibrosis in males, but the underlying mechanisms are still undetermined. In addition, the role of ECM remodeling in HFD associated renal fibrosis needs to be assessed prior to the onset of renal fibrosis.Support or Funding InformationSupported by NHLBI 2P01HL070687 for G.D.F, J.J.G. and H.XThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.