Targeted changes in blood lipids improves fibrosis in renal allografts

Abstract

Background Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. Methods Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson’s trichrome staining were used to determine the degree of fibrosis. Results Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. Conclusions This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.

High-Dose Fenofibrate Stimulates Multiple Cellular Stress Pathways in the Kidney of Old Rats

“…Moreover, we observed an anti-fibrotic action of the lower, but not the higher FF dose only in young rats. This result aligns with reports of FF’s renal anti-fibrotic effects in rodent models of HFD [ 25 ], diabetes [ 6 , 27 , 31 ], ischemia-reperfusion injury [ 32 ], and renal transplants [ 33 , 34 ]. Indeed, it has been suggested that renal lipotoxicity due to elevated blood lipid levels causes transcriptional suppression of PPARα by ATF6α (Activating Transcription Factor 6 alpha), leading to increased expression of connective tissue growth factor involved in fibrosis [ 32 ].…”