Urolithin A Attenuates Hyperuricemic Nephropathy in Fructose-Fed Mice by Impairing STING-NLRP3 Axis-Mediated Inflammatory Response via Restoration of Parkin-Dependent Mitophagy

Abstract

Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression.

Mitophagy, Inflammasomes and Their Interaction in Kidney Diseases: A Comprehensive Review of Experimental Studies

“… 115 In hyperuricemia-induced CKD, PINK1/parkin-mediated mitophagy was impaired, thereby activating NLRP3, resulting in increased production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, leading to RTECs injury. 116 Mitophagy was also activated in angiotensin II-treated RTECs; PHB2 knockdown decreased mitophagy levels and increased cell death, whereas PHB2 overexpression enhanced mitochondrial dysfunction and inhibited NLRP3 inflammasome activation. 117 This suggested that PHB2-mediated mitophagy via the inflammasome may be a future therapeutic target for CKD.…”

Natural products for kidney disease treatment: Focus on targeting mitochondrial dysfunction

“…Accumulated evidences have shown that urolithin A exhibits multiple protective effects inducing mitophagy in heart ( Huang et al, 2022c ), muscle ( Luan et al, 2021 ) and brain ( Jayatunga et al, 2021 ). As a Nrf2 activator, urolithin A not only protects kidney against oxidative stress via promoting Nrf2 translocating into nucleus ( Zhang et al, 2022c ), but also ameliorates hyperuricemic nephropathy via enhancing PINK1-associated mitophagy in renal TECs ( Zhang et al, 2022a ). A study showed that urolithin A treatment restores renal function, and alleviates tubular cell dilation and collagen deposition in glomerular basement membrane ( Zhang et al, 2022a ).…”

Possible correlated signaling pathways with chronic urate nephropathy: A review

“…Anti-inflammatory effects can also be achieved by inhibiting the pre-activation of NLRP3 inflammatory bodies in humans. Zhang [21] urolithione A interferes with STING-NLRP3 axis-mediated HN to achieve anti-inflammation and promote mitochondrial autophagy to further inhibit the activation of STING-NLRP3 axis. The expression of IL-1 β, IL-6 and TNF- α protein decreased in renal tissue and serum.…”