Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice

Abstract

(1) Background: Ischemia reperfusion (IR) is the leading cause of acute kidney injury (AKI) and results in predisposition to chronic kidney disease. We demonstrated that delayed contralateral nephrectomy (Nx) greatly improved the function of the IR-injured kidney and decelerated fibrosis progression. Our aim was to identify microRNAs (miRNA/miR) involved in this process. (2) Methods: NMRI mice were subjected to 30 min of renal IR and one week later to Nx/sham surgery. The experiments were conducted for 7–28 days after IR. On day 8, multiplex renal miRNA profiling was performed. Expression of nine miRNAs was determined with qPCR at all time points. Based on the target prediction, plexin-A2 and Cd2AP were measured by Western blot. (3) Results: On day 8 after IR, the expression of 20/1195 miRNAs doubled, and 9/13 selected miRNAs were upregulated at all time points. Nx reduced the expression of several ischemia-induced pro-fibrotic miRNAs (fibromirs), such as miR-142a-duplex, miR-146a-5p, miR-199a-duplex, miR-214-3p and miR-223-3p, in the injured kidneys at various time points. Plexin-A2 was upregulated by IR on day 10, while Cd2AP was unchanged. (4) Conclusion: Nx delayed fibrosis progression and decreased the expression of ischemia-induced fibromirs. The protein expression of plexin-A2 and Cd2AP is mainly regulated by factors other than miRNAs.

YB-1 Is a Novel Target for the Inhibition of α-Adrenergic-Induced Hypertrophy

“…The source code of the TargetScan algorithm was downloaded from the TargetScanHuman v7.2 webpage, and minor adjustments were applied to be able to run TargetScan with Rattus norvegicus data. Preprocessed and filtered (total context++ score <= −0.2) TargetScan predictions were used as an input interaction database for the theoretical network in miRNAtarget™ software version 2.0 (mirnatarget.com; Pharmahungary, Szeged, Hungary) [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] to combine the effects of the two sequences and to construct an siRNA–target interaction network. Off-target scores were calculated by summing the total context++ scores of the siRNA–target interactions in which the target was predicted to be involved.…”

Focus on oliguria during renal replacement therapy

“…Recently, the term "Permissive azotemia" has been proposed [38]. Recent evidence suggests that decreased renal clearance does result in significant decreases in monocyte/macrophage infiltration, complement levels, oxidative stress, and other markers of inflammation in the injured kidney [39][40][41].…”

Permissive azotemia during acute kidney injury enables more rapid renal recovery and less renal fibrosis: a hypothesis and clinical development plan

“…As compared to non-nephrectomized animals, contralateral nephrectomy in unilateral injured animals showed improved histology as evidenced by less severe necrosis, fewer casts, and less apoptosis [ 3 , 4 , 7 ]. In addition to improved histology, the inflammatory response is lessened by nephrectomy along with lower levels of oxidative stress [ 7 , 8 , 11 ]. The decreases in inflammation and oxidative stress are mirrored by a blunting of the pro-fibrotic response with a marked downregulation of the fibrotic cellular genetic response and decreased activation of pericytes and myofibroblasts [ 7 , 8 , 11 ].…”

“…In addition to improved histology, the inflammatory response is lessened by nephrectomy along with lower levels of oxidative stress [ 7 , 8 , 11 ]. The decreases in inflammation and oxidative stress are mirrored by a blunting of the pro-fibrotic response with a marked downregulation of the fibrotic cellular genetic response and decreased activation of pericytes and myofibroblasts [ 7 , 8 , 11 ]. Also, the renal blood flow to the injured kidney recovers more rapidly and is enhanced by nephrectomy [ 7 , 12 , 13 ].…”

“…Notably, the effect of decreased renal clearance induced by nephrectomy of the healthy kidney initiates a profound change in the contralateral injured kidney whether the injury is due to ischemia/reperfusion (IR) or unilateral ureteral obstruction (UUO) [ 8 , 10 ]. Significant decreases in monocyte/macrophage infiltration, complement levels, oxidative stress, and other markers of inflammation in the injured kidney are observed in addition to improved histology and less fibrosis [ 8 , 10 , 11 ]. These findings have been consistently demonstrated across multiple animal species in the multiple laboratories across the globe.…”