#3532 Bariatric surgery reverses ORG and exhibits a distinct transcriptomic profile compared to weight loss through a low-fat diet

Abstract Background and Aims The therapeutic option of obesity comorbidities has always been weight loss. Clinically relevant weight loss improves clinical parameters of kidney damage, such as proteinuria. However, the histological kidney effects and the gene expression changes after low fat diet (LFD) or bariatric surgery (BS) have never been evaluated. In this project we aim to assess the impact of low fat diet versus bariatric surgery in obesity and obesity related glomerulopathy (ORG). Method 28 rats were randomized into three main groups and fed a high-fat diet (HFD) for 10 weeks when they became obese. Subsequently, 8 obese rats were sacrificed (HFD-group), 8 animals were fed a LFD (LFD-group) during 10 weeks and 12 underwent BS through sleeve gastrectomy (CB-group) and fed a standard diet until the end of the study. Parameters like body weight, measured glomerular filtration rate (mGFR), albuminuria, kidney histological lesions and transcriptomic expression between groups were assessed. Results The LFD-group reduced their weight a 1.58% until 476.16 ± 26.06 gr and the BS-group reached a 13.2% of weight loss 435.61 ± 36.85 gr. The rate of weight loss of the CIR-group was of 2.1 times higher than that of the LFD group. Albuminuria in HFD-group reached 10384.04 ± 1167.96 ng/mL, while in LFD and CIR groups the albuminuria decreased substantially to 7228.04 ± 514.22 (P = 0.008) and 6241.50 ± 418.33 (P = 0.006), respectively. Albuminuria correlated with weight loss (coef R² = 0,78203). Glomerular area was significantly smaller in both LFD (9109.76 ± 1185.51 µm²; P = 0.019) and BS (8218.31 ± 916.72 µm²; P < 0.001) groups compared with HFD-group (10640.92 ± 1220.62 µm²). All the rats of the HFD-group developed ORG, LFD-group also some of the characteristic histologic lesions of ORG (mesangial matrix increase, mesangial cell proliferation, podocyte hypertrophy), while none of the BS-group showed any visible glomerular lesions. Direct comparison of BS and LFD revealed a substantial number of differentially expressed genes (DEGs) with a notable cluster of up-regulated genes. Moreover, there was a differential pattern of small RNAs in both kidney tissue and urine, depending on whether the rats were from the BS or LFD group. While LFD induced transcriptional changes, these were less extensive that after BS, supporting a unique transcriptomic response associated with the surgical intervention. Gene ontology and reactome pathway analyses revealed that both interventions modulate specific pathways related to cellular metabolism (particularly mitochondrial processes), amino acid metabolism, and other biological processes within the kidney. Conclusion Bariatric surgery is much more effective for drastic weight loss than low fat diet in obese rats. Albuminuria in both LFD and BS-groups was significantly reduced and albuminuria correlated with weight loss. Strikingly, this project confirmed for the first time in scientific literature that bariatric surgery reverses all the histological lesions of obesity-related glomerulopathy. Finally, bariatric surgery has a profound impact on renal gene expression. There is a differential pattern of gene expression in kidney tissue, as well as of small RNA in both kidney tissue and urine. Specific pathways such as mitochondrial processes and amino acid metabolism are specifically modulated. These results offer new insights into potential therapeutic strategies for obesity-related kidney disease.