Fig. 9. Modulation of kidney fibrosis in ADTKD-UMOD by MANF.

Mutant UMOD triggers ER stress response, which may directly or indirectly inhibit AMPK activation. Tubular overexpression of MANF after the onset of ADTKD promotes autophagy/mitophagy via activation of p-AMPK-FOXO3 signaling, and enhances mitochondrial biogenesis via p-AMPK-PGC1α axis. Moreover, elimination of dysfunctional mitochondria and restoration of mitochondrial homeostasis through increased tubular MANF expression abrogate STING activation and mitigate tubular pathological inflammation. Finally, increased autophagic clearance of mutant UMOD by tubular MANF upregulation would further stop the malicious cycle between impaired autophagy and ER stress intensification, eventually protecting kidney function in ADTKD-UMOD.