Upregulation of the Urotensin II System in Diabetic Kidney Disease Includes Urotensin II-Related Peptide

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The urotensin II (UII) system consists of endogenous ligands UII and its paralog urotensin II-related peptide (URP) and their receptor, UT. Originally isolated from the rat brain, URP is conserved across all vertebrates and shares the same cyclic hexapeptide core sequence with UII. However, UII and URP exhibit different N-terminal amino acid sequences. Beyond the central nervous system, UII and URP are functionally expressed in peripheral tissues. Alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been associated with cardiovascular, pulmonary, and kidney dysfunctions, including hypertension, chronic heart failure, pulmonary hypertension, glomerulonephritis, and diabetes, making the UII system a potential therapeutic target for cardiovascular and kidney disease. The skeletal muscle and plasma levels of UII are increased in diabetic mice. Increased kidney tissue expression levels of UII and UT have also been demonstrated in humans and animals with diabetic kidney disease (DKD). Our recent work showed that UT is functionally expressed in cultured mouse glomerular mesangial cells (GMCs). Activation of UT by UII contributes to Ca2+-dependent GMC proliferation and extracellular matrix protein accumulation under high glucose conditions. We have also shown that DKD is attenuated in UT knockout mice. Despite the structural homology between UII and URP, studies have shown that the peptides may exhibit differential central and peripheral expression and pathophysiological function. However, whether URP is dysregulated in DKD remains unclear. Here, we examined whether URP production and kidney expression levels are altered in a hyperglycemic milieu and associated with DKD. Using a streptozotocin (STZ)-induced diabetes model, we examined the kidney tissue, plasma, and urinary levels of UII peptides. We also tested the hypothesis that, like UII, URP stimulates GMC proliferation and matrix protein synthesis. Our data show that protein and mRNA expression levels of both UII and URP were increased in the kidneys of hyperglycemic mice that developed albuminuria. Urinary and plasma UII and URP concentrations were also elevated in the mice. Although both UII and URP stimulated proliferation and type IV collagen production in cultured mouse GMCs by activating UT, the effect of UII was greater. Our data suggests that changes in the UII system in DKD are not limited to UII and UT but include the less-studied URP. GMC proliferation and extracellular matrix accumulation driven by UII and URP may contribute to DKD. NHLBI: R01 HL151735. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.