FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity

Abstract

Chronic kidney disease (CKD) has reached epidemic proportions worldwide, partly due to the increasing population of elderly and obesity. Macroautophagy/autophagy counteracts CKD progression, whereas autophagy is stagnated owing to lysosomal overburden during aging and obesity, which promotes CKD progression. Therefore, for preventing CKD progression during aging and obesity, it is important to elucidate the compensation mechanisms of autophagy stagnation. We recently showed that FGF21 (fibroblast growth factor 21), which is a prolongevity and metabolic hormone, is induced by autophagy deficiency in kidney proximal tubular epithelial cells (PTECs); however, its pathophysiological role remains uncertain. Here, we investigated the interplay between FGF21 and autophagy and the direct contribution of endogenous FGF21 in the kidney during aging and obesity using PTEC-specific <i>fgf21</i>- and/or <i>atg5</i>-deficient mice at 24 months (<i>aged</i>) or under high-fat diet (<i>obese</i>) conditions. PTEC-specific FGF21 deficiency in <i>young</i> mice increased autophagic flux due to increased demand of autophagy, whereas <i>fgf21</i>-deficient <i>aged</i> or <i>obese</i> mice exacerbated autophagy stagnation due to severer lysosomal overburden caused by aberrant autophagy. FGF21 was robustly induced by autophagy deficiency, and <i>aged</i> or <i>obese</i> PTEC-specific <i>fgf21</i>- and <i>atg5</i>-double deficient mice deteriorated renal histology compared with <i>atg5</i>-deficient mice. Mitochondrial function was severely disturbed concomitant with exacerbated oxidative stress and downregulated TFAM (transcription factor A, mitochondrial) in double-deficient mice. These results indicate that FGF21 is robustly induced by autophagy disturbance and protects against CKD progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis, which will pave the way to a novel treatment for CKD.