Glomerular hyperfiltration and enhanced sensitivity to kidney ischemia reperfusion with a blunted KIM-1 response in...

To better understand the impact of accelerated aging on kidney function, we compared standard C57BL6 mice (C57BL6) with senescence-accelerated mouse-prone 8 mice (SAMP8). Young male SAMP8 (3 and 6 mo) showed glomerular hyperfiltration compared with C57BL6 (absolute and per body weight), followed by gradual glomerular filtration rate (GFR) decline, lower blood pressure, and enhanced mortality over the first 15 mo of life. This was associated with higher kidney, heart, and liver but not brain weights. Female SAMP8 likewise showed a faster early rise in body weight, higher organ weights, and a somewhat higher mortality, but GFR and blood pressure appeared unaltered versus C57BL6. Since GFR phenotype was stronger in male mice, they were subjected to bilateral renal artery clamping-induced kidney ischemia reperfusion (IR). One day after IR, young SAMP8 (3 mo) showed higher plasma creatinine and kidney VCAM1 expression and subsequent mortality but a blunted rise in kidney Kim-1 mRNA and urine KIM-1 versus C57BL6. Kidney proteomics indicated suppressed pathways of phagocytosis and apoptosis but enhanced necroptosis in SAMP8 versus C57BL6. When ischemia time was lowered in SAMP8 to induce a similar initial rise in plasma creatinine and urine NGAL versus C57BL6, plasma creatinine recovery over 24 days was similar between strains in young mice, and despite impaired plasma creatinine recovery in older SAMP8 (10 mo) kidney injury or inflammation seemed not enhanced. In conclusion, male SAMP8 mice have a shortened life span, large kidneys, and at young age temporal hyperfiltration and enhanced sensitivity to IR-induced acute kidney injury associated with a blunted KIM-1 response.NEW & NOTEWORTHY The impact of accelerated aging on kidney function is incompletely understood. The current work shows that male mice of an accelerated aging mouse strain have a shortened lifespan that is associated with large kidneys. At young age, the mice have temporal glomerular hyperfiltration, reminiscent of the early diabetic kidney, and show enhanced sensitivity to renal ischemia reperfusion-induced acute kidney injury associated with a blunted upregulation of the tubular injury marker KIM-1.