Potential Role of Secretin and Its Receptor in Kidney Disease Progression

Background: Secretin, traditionally considered a gastrointestinal hormone, has recently been shown to elicit a substantial modulatory effect on renal glomerular filtration mediated through dilation of the efferent arteriole. Congruently, loss of the receptor leads to glomerular hyperfiltration, a condition that entails irreversible kidney damage over time. This study aims to investigate whether secretin and its receptor play a role in the development of renal disease. Methods: The effects of an abolished secretin response on kidney and cardiovascular function were investigated using the secretin receptor (SCTR) KO mice. SCTR KO and WT mice were examined during normal ageing and after subjection to a hypertensive and a western diet challenge. Changes in renal and cardiovascular function were assessed via transcutaneous GFR, blood pressure, echocardiography, urine and blood analysis, western blotting and tissue staining. Results: Under baseline conditions, SCTR KO and WT mice had similar blood pressure and cardiac function. KO mice had elevated GFR when young but showed a marked age-dependent GFR decline compared to WTs. In kidney tissue from 1-year-old KO and WT mice, KOs had elevated mRNA levels of collagen 1a1 and collagen 3, indicative of ongoing renal fibrosis and damage. Concordantly, KOs had significantly elevated protein levels of aSMA and fibronectin on western blot. When challenged with a Western diet, both KOs and WTs developed proteinuria, and the KOs became hypertensive while the WTs remained normotensive. Data from the hypertensive challenge is pending. Conclusion: Based on the results, SCTR KO mice exhibit a phenotype indicative of progressive renal disease. The phenotype progresses with normal ageing and is slightly exacerbated by a dietary challenge. Further in vivo and ex vivo experiments have commenced, expanding on the current findings.