Fig. 4 | Nature Communications

Fig. 4

From: Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease

Fig. 4

TPL inhibitors lowered PS concentrations and reduced renal damage in mouse models of diabetic kidney disease and adenine-induced renal failure. a Scheme of gut microbiome-derived PS, PCS, and IS generation. Dietary tyrosine is converted to phenol by tyrosine phenol-lyase (TPL) and further modified to produce PS or PCS. Dietary tryptophan is first converted to indole by tryptophan indole-lyase (TIL), further converted and finally modified into IS. Specific inhibitors of TPL are 2-aza-tyrosine and l-meta-tyrosine, while homo-BZI-Ala is a specific inhibitor of TIL. b Plasma concentrations of PS, IS, PCS, TMAO, and Cr in db/db mice before (Pre) and after treated with 2-aza-tyrosine (post, 10 mg/kg, n = 10). c Urinary albumin/creatinine ratio of db/db mice with either no intervention (Ctrl) or treatment with the TPL inhibitor 2-aza-tyrosine (AZA). N = 6 in each group. d Plasma concentrations of PS, IS, PCS, TMAO, and Cr in the adenine-induced renal failure mouse model treated with 2-aza-tyrosine (5 mg/kg) for 14 days. Four groups were measured: control mice (Ctrl), control mice treated with 2-aza-tyrosine (AZA), adenine-induced renal failure mice with no intervention (RF), and adenine-induced renal failure mice treated with 2-aza-tyrosine (RF-AZA). n = 5 in each group. e Representative imaging mass spectrometry spectra of PS and IS in kidney sections from renal failure mice (RF) and renal failure mice administered 2-aza-tyrosine (5 mg/kg) (RF + AZA). Mass spectrometry imaging shows the distribution of PS ([M-H], m/z 172) and IS ([M-H], m/z 212). Scale bar, 1000 μm. f Quantitative analysis of PS and IS tissue contents in mouse kidneys in RF (n = 4) and others (n = 5). g Morphometric analysis of the fractional cortical tubular area of Masson trichrome stained whole kidney images. n = 5 in each group. Data are presented as the percentage of the total cortex (n = 5). Scale bar, 500 μm. h Enzymatic activity of TIL. TIL activity under control conditions (Ctrl), with TIL inhibitor homo-BZI-Ala (100 μM) and a tyrosine phenol-lyase inhibitors (l-meta-tyrosine (LmT) or 2-aza-tyrosine (AZA), 1 mM), n = 3. *p < 0.05 vs. control according to Paired t test (b), data are mean ± SEM *p < 0.05 vs. control according to t test (c, d, g, f) or Tukey–Kramer test (h, *p < 0.05, **p < 0.01, ***p < 0.001). Source data are provided as a Source Data file

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