Complete renal denervation protects against aristolochic acid nephropathy

Aristolochic acid nephropathy (AAN) is a kidney disease characterized initially by tubulointerstitial nephritis and inflammation and eventually by fibrosis and end stage renal disease. Upregulated renal sympathetic nerve activity occurs in various forms of chronic kidney disease (CKD) and may contribute to both hypertension and kidney disease progression. We hypothesized that complete afferent and efferent renal denervation would protect against damage and loss of kidney function in an acute model of AAN. To test this, renal denervation (RDN) or sham surgery was performed on C57Bl/6J mice. RDN was performed by surgical transection of all visible renal nerves followed by application of 10% phenol in 90% ethanol to the renal artery and vein. The surgery was followed by intraperitoneal injections of aristolochic acid (5 mg/kg) or vehicle three days a week for two weeks. Three days after the final injection, the glomerular filtration rate (GFR) of each mouse was determined. Mice were euthanized and kidneys were assayed for markers of injury, fibrosis, and inflammation. Overall kidney function after injury was improved by denervation, as GFR in RDN AAN mice was significantly improved compared to sham AAN (427.4 µL/min/100g body weight ± 40.1 vs. 204.1 ± 4.2, p < 0.05). Furthermore, RDN mice had significantly lower serum creatinine (0.32 mg/dL ± 0.05 vs. 0.77 mg/dL ± 0.07, p < 0.05) and blood urea nitrogen (27.0 mg/dL ± 3.46 vs. 41.72 mg/dL ± 1.47, p < 0.05) than controls. While kidney injury markers were elevated after AAN in all mice, we found a significant reduction in neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), IL-1β, fibronectin, α-smooth muscle actin, collagen 1, and tenascin C mRNA in mice that underwent RDN compared to sham surgery. Fibronectin protein was also significantly reduced in the RDN group. Our data suggest that renal nerves play a pathologic role in the development and progression of AAN CKD and that renal denervation could be a novel treatment for this disease. NIH NIDDK R01DK131991; NIDDK R01DK064005; NIDDK U54DK137329 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.