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

Bibi S Van Thiel,Michael Bader,A H Jan Danser,Jeroen Essers,Ingrid Van Der Pluijm,Janette Van Der Linden,Marian C Clahsen-Van Groningen,Natalia Alenina,Yanto Ridwan,Anton J M Roks,Marcel Vermeij,Fatimunnisa Qadri,Ingrid M Garrelds

doi:10.3390/ijms222212433

Abstract

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 Ercc1d/− 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 Ercc1d/− mice, while initial renal development was normal. Next, we examined the in vivo renin activity in these Ercc1d/− mice. Interestingly, increased intrarenal renin activity was detected by ReninSense in Ercc1d/− 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.

Highlights

Aging is a natural biological process that is associated with diverse detrimental changes in cells and tissues, leading to loss of organ function
Ercc1d/− mice display progressive kidney pathology, including tubular degeneration, loss of brush borders and anisokaryosis (Figure 1), and a significantly increased acute tubular necrosis (ATN) score (Figure 2b). They present with signs of kidney aging, as shown by reduced proliferation and increased apoptosis (Figure 2c) at 24 weeks of age
At 6 weeks of age, urinary albumin, creatinine and urea levels were significantly lower in Ercc1d/− mice compared to WT littermates, urea/creatinine ratio levels were comparable to WT mice, which did not imply renal dysfunction

Summary

Introduction

Aging is a natural biological process that is associated with diverse detrimental changes in cells and tissues, leading to loss of organ function. Many elderly show a decline in renal function, often shown as progressive decreases in glomerular filtration rate and renal blood flow. These age-related structural and functional changes may predispose the kidneys to acute kidney injury or progressive chronic kidney disease [2]. Changes in the responsiveness and activity of the RAS have been shown to play an important role in aging, as well as in renal disease, as they predispose the elderly to acute kidney injury and chronic kidney disease [3,4,5,6,7]. Interference in the RAS system by using RAS blockers has been proposed to extend the lifespan and prevent age-associated changes [10]

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