Renal denervation protects against tacrolimus-induced renal dysfunction in Sprague Dawley rats through modulation of renin activity and calcium-channel signaling

Tacrolimus is the most widely-used immune suppressant medication after solid organ transplantation (SOT), however its use is complicated by the development of chronic kidney disease. This disease is less prevalent and less severe in patients with kidney transplants than in other SOT. We hypothesized that the transplanted kidney’s relative protection was conferred by their lack of renal nerves and tested this hypothesis in a rat model of tacrolimus nephrotoxicity. Sprague-Dawley (SD) rats underwent either renal denervation (RDN) or sham surgery and then were treated for 2 weeks with either tacrolimus (2 mg/kg) or vehicle (corn oil). RDN rats exhibited significantly lower BUN than sham rats (24 vs 36 mg/dl, n=6, p<0.05) indicating maintenance of filtration function. To evaluate whether the mechanism behind this protection was renal in origin, we next investigated unilaterally denervated rats, in which one kidney underwent RDN and the other was sham treated. In this way, we have paired kidneys in which they are exposed to the same cardiovascular parameters, circulating hormones, etc, and the only difference is due to the innervation of the kidney directly. After 2 weeks of tacrolimus treatment, the denervated kidney exhibited 2-fold higher inulin clearance than the contralateral sham kidney (n=6, p<0.01). Cortexes from these unilaterally denervated kidneys were isolated and RNA was sequenced from these cortexes. RNAseq analysis reveals 1421 genes significantly differentially regulated between the RDN and sham kidneys (n=5, p<0.05). Pathway analysis of these genes revealed significant overrepresentation in the renin secretion pathway (10 genes, q <0.1) the calcium signaling pathway (24 genes, q<0.1) among others, with both renin signaling and calcium signaling suggested to be lower in the denervated kidney than the sham kidney. Together our results demonstrate RDN’s protection against tacrolimus nephrotoxicity, demonstrate that this protection is mediated by an intrinsic renal mechanism, and nominate pathways by which this protection is mediated. Future studies will further define this protection and pave the way for translation to human trials in the non-renal SOT population. AD is funded by T32HL144472. LE is funded by R01HL152166. JO is funded by R01HL116476. 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.