Fig. 8: Renal tubular upregulation of MANF promotes mitophagy and improves mitochondrial biogenesis, leading to abrogation of STING activation and kidney fibrosis in ADTKD-UMOD. | Nature Communications

Fig. 8: Renal tubular upregulation of MANF promotes mitophagy and improves mitochondrial biogenesis, leading to abrogation of STING activation and kidney fibrosis in ADTKD-UMOD.

From: MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Fig. 8

a WBs of PINK1, Parkin and BNIP3L (arrow) in TALs isolate from the kidneys of the indicated groups at 12 weeks with densitometry analysis. For WT, DEL/ + ;P8TA, DEL/ + ;MANF/P8TA, n = 4, 6, 4 for PINK1, n = 3, 3, 3 for Parkin and BNIP3L. One-way ANOVA with Tukey’s multiple comparisons, Mean ± SD. DEL/ + ;P8TA vs WT: p < 0.0001 (PINK1), 0.0007 (Parkin) and 0.0005 (BNIP3L). DEL/ + ;MANF/P8TA vs DEL/ + ;P8TA: p = 0.0011 (for PINK1), 0.0141 (Parkin) and 0.0125 (BNIP3L). b WB of PGC1α in TALs from the indicated groups at 12 weeks. c Transcript analysis of mt-Nd4, mt-Co1, mt-CytC and mt-Rnr2 from TALs of WT (n = 4–7), DEL/ + ;P8TA (n = 4) and DEL/ + ;MANF/P8TA (n = 3) at 16 weeks. One-way ANOVA with Tukey’s multiple comparisons, Mean ± SD. ****p < 0.0001. DEL/ + ;MANF/P8TA vs DEL/ + ;P8TA: *p = 0.031 (for mt-Nd4), 0.0115 (mt-Co1), 0.0357 (mt-CytC) and 0.0248 (mt-Rnr2). d WBs of ETC expression in TALs of the indicated genotypes at 16 weeks. e Assessment of mitochondrial function using an OROBOROS Oxygraph system in permeabilized TALs of WT (n = 3), DEL/ + ;P8TA (n = 5) and DEL/ + ;MANF/P8TA (n = 4) at 16 weeks following sequential additions of G + M + P; ADP; succinate and FCCP. One-way ANOVA with Tukey’s multiple comparisons, Mean ± SD. DEL/ + ;P8TA vs WT: **p = 0.0085, ****p < 0.0001. DEL/+;MANF/P8TA vs DEL/ + ;P8TA: p = 0.8880 (ns, G + M + P), 0.0095 (ADP), 0.0017 (Succinate), 0.0052 (FCCP). f WBs of STING signaling in the TALs of the indicated genotypes at 16 weeks. g Transcript analysis of inflammatory genes from TALs of WT (n = 4-6), DEL/ + ;P8TA (n = 4 for Il1b, Icam1, n = 5 for Tnfa, Il6) and DEL/ + ;MANF/P8TA (n = 3) at 16 weeks. One-way ANOVA with Tukey’s multiple comparisons, Mean ± SD. h WBs of NGAL and FN in the kidneys of the indicated genotypes at 20 weeks. i Trichrome staining of kidney sections from the indicated groups at 20 weeks with quantification. n = 8 images/genotype. One-way ANOVA with Tukey’s multiple comparisons, Mean ± SD. ****p < 0.0001. Source data are provided as a Source Data file.

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