Unilateral nephrectomy diminishes ischemic acute kidney injury through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses

Abstract

While unilateral nephrectomy (UNx) is suggested to protect against ischemia-reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia. MRI was performed 24 hours after reperfusion. Blood and renal tissue were harvested. RNA was isolated for microarray analysis and QPCR validation of gene expression results. The perfusion (T1 value) was significantly enhanced in the medulla of the post-ischemic kidney following UNx. UNx decreased the expression of fibrogenic genes, i.a. Col1a1, Fn1 and Tgfb1 in the post-ischemic kidney. This was associated with a marked decrease in markers of activated myofibroblasts (Acta2/α-Sma and Cdh11) and macrophages (Ccr2). This was most likely facilitated by down-regulation of Pdgfra, thus inhibiting pericyte-myofibroblast differentiation, chemokine production (Ccl2/Mcp1) and macrophage infiltration. UNx reduced ischemic histopathologic injury. UNx may exert renoprotective effects against IRI through increased perfusion in the renal medulla and alleviation of the acute pro-inflammatory and pro-fibrotic responses possibly through decreased myofibroblast activation. The identified pathways involved may serve as potential therapeutic targets and should be taken into account in experimental models of IRI.

A Pilot Study of Postoperative Animal Welfare as a Guidance Tool in the Development of a Kidney Autotransplantation Model With Extended Warm Ischemia

“…2,11,13-17 In addition, it is well known that removal of 1 kidney will stimulate an increase of renal perfusion and GFR with compensatory growth of the remaining kidney. 48 A 1-kidney GFR of 38 and 40 mL/min is below normal range for this size of pigs and represents a state of renal damage when compared with older studies. Frennby et al 49 measured GFR in 1-kidney pigs with reduced renal function and found a median GFR of 30 mL/min/50 kg, supporting this interpretation.…”

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

“…Therefore, the increased humoral load and tubular hypertrophy observed in the contralateral kidney may serve as a form of injury that triggers accumulation of macrophages leading to accelerated cystogenesis. Because UNx in wild-type mice does not increase the number of macrophages (44), the accumulation of kidney macrophages upon UNx specifically occurs in the absence of Pkd1. An interesting observation of these studies is data showing that treatment of 1K Pkd1 mice with IRF5 ASO significantly reduced cystic index (i.e., cyst size), but did not affect cyst number.…”

A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

“…Unilateral nephrectomy was shown to diminish ischemic AKI through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses. 68 The preventive setting revealed a crucial role of CYP-eicosanoids in AKI initiation; however, further studies are needed to prove the therapeutic potential of EET analogues in decreasing renal injury after the ischemic event had occurred.…”

“…68 The preventive setting revealed a crucial role of CYP-eicosanoids in AKI initiation; however, further studies are needed to prove the therapeutic potential of EET analogues in decreasing renal injury after the ischemic event had occurred. Unilateral nephrectomy was shown to diminish ischemic AKI through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses.…”