Kidney Vascular Remodeling And Brain Vascular Contractility In Kidney Injury

Part one:The Mechanism of Outward Remodeling of Efferent Arterioles Induced by Chronic Kidney InjuryAim:The glomerular filtration rate(GFR)falls progressively in chronic kidney disease(CKD)and a lower glomerular capillary pressure that is determined by a functional balance between renal afferent and efferent arterioles may be a cause.Therefore,we tested the hypothesis that oxidative stress induced by CKD differentially impairs the structure or function of efferent versus afferent arterioles.Methods:C57BL/6 mice received sham operations(sham)or 5/6 nephrectomy(reduced renal mass,RRM)and 3 months of normal diet,high salt diet or high salt diet plus tempol.GFR was assessed from the plasma inulin clearance.Urine albumin and oxidative stress level were assessed from the urine enzyme linked immunosorbent assay(ELISA).The weight of the remaining kidney tissue was weighted and glomerular volume was assessed from histochemistry,arteriolar remodeling from media/lumen area ratio and myogenic responses from changes in luminal diameter with increases in perfusion pressure.Results:Mice with RRM fed a high salt(versus sham fed a normal salt)had a lower GFR,a higher urine albumin and oxidative stress level and a higher remaining kidney tissue weight and glomerular volume.A higher efferent arteriolar luminal diameter resulting in a lower media/lumen area ratio.Except the remaining kidney tissue weight and glomerular volume,all these alterations were corrected by tempol.The myogenic responses of efferent arterioles were about one-half that of afferent arterioles and were unaffected by RRM and/or salt alone.Conclusion:A reduction in renal mass with a high salt diet induces oxidative stress that leads to an outward remodeling in efferent arterioles.This may contribute to the lower GFR in this model of CKD.Part two:Resetting of Brain Vascular Reactivity to Angiotensin ?by Fibroblast Growth Factor Receptor Inhibitor after Acute Kidney InjuryAim:Acute kidney injury(AKI)is a common complication with high morbidity and mortality.Since AKI often coexists with multiple organ failure,focusing on the kidney damage has not been sufficient.Here,we tested the hypothesis that fibroblast growth factor 2(FGF2,bFGF)promotes brain injury in AKI by sensitizing the angiotensin ?(Ang ?)response of brain vessels and this may be one of the most important causes of AKI morbidity and mortality.Methods:Kidney and brain tissues were isolated and tested 24 h after 30 min bilateral renal ischemia-reperfusion injury.The overall condition of kidney and brain tissues was assessed by detecting oxidative stress,inflammation and angiogenesis level.Response to Ang ? or other vasoconstrictors were assessed by measuring brain vascular diameter.The mRNA and protein expressions of FGF2,fibroblast growth factor binding protein 1(FGFBP1),related FGF receptor(FGFR)and Ang ? receptors,downstream signaling molecules and inflammatory associated proteins were assessed in vessels and tissues of both kidney and brain.Results:We found that only the Ang ? response was enhanced in brain vessels after AKI and this effect was further amplified by treatment with both FGF2 and FGFBP1.Complementary to this,the selective inhibitors of the FGFR tyrosine kinase decreased the Ang ? response in brain vessels both in vivo and in vitro after AKI indicating a crosstalk between the Ang ? and the FGF receptor pathway.Oxidative stress and inflammation may play an important role in facilitating in this process.Conclusion:We conclude that the synergism between the Ang ? and FGFR signaling pathway may be one of the reasons for brain injury after AKI and FGFRs maybe a new target for preventing AKI induced brain damage.