Mechanism of Disease Progression by Renin Overexpression in the db/db-UNx Model: A Proteomic Analysis

Background: The db/db-UNx-renin model has gained in popularity, showing both increased albuminuria and reduced glomerular filtration rate (GFR). Our aim was to characterize the renal injury of db/db-UNx-renin mice using proteomics and to understand the role of renin overexpression in disease progression. Methods: Four weeks-old db/db mice were subjected to uninephrectomy, two weeks later received an intravenous injection of an AAV containing either an empty vector or the human renin gene and the experiment was terminated at 16 weeks of age. Albuminuria was measured every two weeks, renal oxygen content and renal volume and transcutaneous GFR were determined at the end of the experiment. The remaining kidney was harvested, and proteomics analysis performed on the cortical fraction. Results: Compared to db/m mice, GFR and renal oxygenation were increased in db/db-UNx mice, indicating a state of hyperfiltration. Renin overexpression caused a significant reduction in GFR in these mice. In db/db-UNx mice, albuminuria progressed throughout the experiment, while in db/db-UNx-renin mice, albuminuria peaked 2 weeks after AAV-renin injection and remained high. Renal hypertrophy was evident in db/db-UNx mice while cardiac hypertrophy was only observed in db/db-UNx-renin mice. Proteomics analysis of renal cortex showed that pathways associated with protein synthesis, energy metabolism, transport activity, mitochondria and respiration, adipogenesis and glycolysis and gluconeogenesis and amino acid metabolism were activated in db/db-UNx mice, suggesting a metabolic adaptation to the hyperfiltration seen in these mice. Renin overexpression, on the other hand, activated pathways associated with renal injury, extracellular matrix remodeling, inflammation, complement activation, macrophage activation, secretion of pro-angiogenic and pro-proliferative factors, and clot formation. Conclusion: This study sheds light on the mechanism of kidney injury during diabetes and distinguishes two phases of the disease. In the hyperfiltrating phase, the renal tubules adapt by increasing their transport activity and energy production, while activation of complement, inflammation and coagulation pathways seem to play a role in the disease progression phase caused by renin overexpression.