Glomerular hyperfiltration and enhanced sensitivity to kidney ischemia reperfusion with a blunted KIM-1 response in young male aging-accelerated SAMP8 mice

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&6 months) showed glomerular hyperfiltration compared with C57BL6 (absolute and per body weight), followed by gradual GFR decline, lower blood pressure, and enhanced mortality over the first 15 months 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 vs. 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 months) showed higher plasma creatinine and kidney VCAM1 expression and subsequent mortality but a blunted rise in kidney Kim-1 mRNA and urine KIM-1 vs. C57BL6. Kidney proteomics indicated suppressed pathways of phagocytosis and apoptosis but enhanced necroptosis in SAMP8 vs C57BL6. When ischemia time was lowered in SAMP8 to induce a similar initial rise in plasma creatinine and urine NGAL vs. C57BL6, plasma creatinine recovery over 24 days was similar between strains in young mice, and despite impaired plasma creatinine recovery in older SAMP8 (10 months) 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.