Gut microbial-derived short chain fatty acids enhance kidney proximal tubule cell secretory function

Abstract

The organic anion transporter-1 (OAT1), located at the basal side of kidney proximal tubule cells, is actively involved in metabolic waste excretion. During chronic kidney disease (CKD), the progressive decline in renal function, results in the accumulation of endogenous metabolites in the bloodstream, exacerbating comorbidities. CKD also leads to gut dysbiosis, resulting in an increased production of uremic metabolites and a reduced production of nephroprotective short chain fatty acid (SCFAs), mainly acetate, propionate and butyrate, thereby contributing to disease progression. Here, we studied the potential of SCFAs to enhance kidney function by modulating OAT1 activity, thereby facilitating uremic toxins secretion. Our findings demonstrate that propionate and butyrate significantly boost OAT1 activity by upregulating SLC22A6/ OAT1 gene and protein expression, with butyrate enhancing the secretion of the uremic toxin indoxyl sulfate to the luminal compartment in our kidney-on-chip (KoC) system. Interestingly, SCFAs function independently of G-protein coupled receptor (GPCR) activation, inhibiting gene expression of class II histone deacetylases (HDACs). Transcriptome analysis suggests that such inhibition modulates cyclic AMP signaling pathway, activating CREB1 and PI3K gene expression, both implicated in cell metabolism and resilience against stress, enhancing cellular fitness. These findings highlight the therapeutic potential of SCFAs in enhancing proximal tubule secretory activity, emphasizing their value as nutritional interventions in CKD management. HIGHLIGHTSO_LIOAT1 activity is boosted by SCFAs via SLC22A6 gene and protein upregulation C_LIO_LISCFAs act independently of GPCRs activation in proximal tubule cells C_LIO_LIHDAC inhibition by SCFAs regulates cAMP pathway modulating CREB1 and PI3K expression C_LIO_LISCFAs have the potential to serve as a therapeutic approach for kidney disease treatment C_LI