In Vivo Renin Activity Imaging in the Kidney of Progeroid Ercc1 Mutant Mice

• Published in: International journal of molecular sciences Vol. 22; no. 22; p. 12433
• Main Authors: van Thiel, Bibi S, van der Linden, Janette, Ridwan, Yanto, Garrelds, Ingrid M, Vermeij, Marcel, Clahsen-van Groningen, Marian C, Qadri, Fatimunnisa, Alenina, Natalia, Bader, Michael, Roks, Anton J M, Danser, A H Jan, Essers, Jeroen, van der Pluijm, Ingrid
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.11.2021; MDPI
• Subjects: Accelerated aging tests; Age; Aging; Aging - genetics; Aging - metabolism; Aging - pathology; Angiotensin; Angiotensin II - genetics; Angiotensin II - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Apoptosis; Blood pressure; Creatinine; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Endonucleases - deficiency; Endonucleases - genetics; ERCC1 protein; Female; Fluorescent indicators; Gene Expression Regulation; Geriatrics; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; Homeostasis; Humans; Hypertension; in vivo imaging; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; Losartan - pharmacology; Male; Medical imaging; Mice; Mice, Knockout; Older people; Pathology; Phenotypes; Plasma; Progeria - genetics; Progeria - metabolism; Progeria - pathology; renal aging; renal disease; Renal failure; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Renin; Renin - genetics; Renin - metabolism; renin-angiotensin system; Renin-Angiotensin System - genetics; Rodents; Signal Transduction; in vivo imaging; renal aging; renin; renal disease; renin-angiotensin system
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222212433

Changes in the renin-angiotensin system, known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. While the renin-angiotensin system is suppressed during aging, little is known about its regulation and activity within tissues. However, this knowledge is required to successively treat or prevent renal disease in the elderly. Ercc1 is involved in important DNA repair pathways, and when mutated causes accelerated aging phenotypes in humans and mice. In this study, we hypothesized that unrepaired DNA damage contributes to accelerated kidney failure. We tested the use of the renin-activatable near-infrared fluorescent probe ReninSense680™ in progeroid mice and compared renin activity levels in vivo to wild-type mice. First, we validated the specificity of the probe by detecting increased intrarenal activity after losartan treatment and the virtual absence of fluorescence in renin knock-out mice. Second, age-related kidney pathology, tubular anisokaryosis, glomerulosclerosis and increased apoptosis were confirmed in the kidneys of 24-week-old mice, while initial renal development was normal. Next, we examined the in vivo renin activity in these mice. Interestingly, increased intrarenal renin activity was detected by ReninSense in compared to WT mice, while their plasma renin concentrations were lower. Hence, this study demonstrates that intrarenal RAS activity does not necessarily run in parallel with circulating renin in the aging mouse. In addition, our study supports the use of this probe for longitudinal imaging of altered RAS signaling in aging.