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Abstract Background and Aims The role of hypertension in CKD is complex. Hypertensive nephropathy or arterionephrosclerosis is caused by prolonged periods of poorly controlled high blood pressure and is characterized by gradual loss of kidney function with various grades of proteinuria over a period of many years. This complexity requires novel analysis strategies for a successful understanding of pathomechanisms, drug target and biomarker identification including well characterized translatable models where the DalhS rats could be relevant. Method We analysed the urinary proteome of hypertensive Dahl S rats at baseline and 2, 4, and 7-weeks of high salt diet (4%, n = 5 in each cohort). A TMT MS/LC method was performed to obtain proteomics profile of the urine, to then filter, normalize and apply a differential analysis based on linear models and empirical Bayes statistics (limma) in R language. Additionally, we did a pathway enrichment analysis using IPA. Finally, to assess the translatability of the findings, we compared the rat urinary proteome data with publicly available urinary proteome from patients with CKD. Results The DalhS rats developed hypertension, proteinuria, and glomerulosclerosis. In the urine, we identified a total of 36 differentially expressed proteins comparing 4 weeks of high salt diet (HSD) versus the baseline, and 85 differentially expressed proteins at 7 weeks of HSD. Pathway analysis of the differentially abundant urinary proteome showed robust enrichment of pathways related to hypertensive kidney damage including ‘acute phase response signaling’, a pathway that activates rapidly in inflammatory settings and can sustain chronically, and liver / retinoid-x-receptor (LXR/RXR) activation, which was also activated. Additionally, the coagulation system and complement cascade also showed positive z-scores in high-salt-exposed rats (after 7 weeks). Moreover, we observed an inactivation of several immune related pathways such as IL-12 signaling and STAT3 pathways. Finally, analysis of publicly available data of the urinary proteome of CKD patients (PMID 34963468, N = 40) exhibited enrichment of more than 20 pathways in common with the DalhS cohort, suggesting a high translatability between the urinary proteome of the animal model and patients. Specifically, we observe activation of acute phase response signalling, LXR/RXR activation, and complement cascade in DalhS and human datasets, as well as inhibition of IL-12 and STAT3 signaling pathways. Conclusion Molecules targeting the complement pathway are under intensive development. Prior development of LXR agonists have been limited by Ph1 findings. The findings with acute-phase response, IL-12 and STAT3 pathways suggests the importance of immune-driven damage mechanisms in hypertensive CKD. Identified proteins and enriched pathways in this work provide a rich resource for future investigation. In conclusion, the Dahl S rat model urinary proteome captures multiple underlying mechanisms of the human hypertensive CKD phenotype.
Hossain et al. (Wed,) studied this question.