Rho Kinase Inhibitor, Fasudil, Attenuates Contrast‐induced Acute Kidney Injury

Abstract

In this study, we tested the hypothesis that fasudil, a Rho kinase inhibitor, would protect against contrast-induced acute kidney injury (CI-AKI) in a mouse model and attempted to elucidate the mechanism involved. Mice subjected to unilateral ligation of the left anterior renal pedicle were divided into four groups: (1) control group, (2) CI-AKI induced by contrast media (CM group), (3) CI-AKI plus low-dose fasudil (LD group) and (4) CI-AKI plus high-dose fasudil (HD group). Animals from groups 2-4 received iodixanol (4.0 g iodine/kg), and the control group received saline. At 12, 2 hr before iodixanol injection and 4 hr after iodixanol administration, the animals in groups 3-4 received 3 or 10 mg/kg fasudil, respectively. Renal blood flow, renal function parameters, kidney histology and the expression of proteins that regulates apoptosis and inflammation were determined 24 hr later. Fasudil treatment notably ameliorated contrast medium-induced medullary damage, restored renal function, suppressed renal tubular apoptosis, ameliorated redox imbalance and DNA damage. Fasudil had a nephroprotective effect that was partially attributed to its anti-inflammatory, anti-apoptotic and antioxidant effects of inhibiting the Rho/ROCK pathway.

Contrast-induced nephropathy and oxidative stress: mechanistic insights for better interventional approaches

“…Moreover, apoptosis was decreased via a reduction in cleaved caspase-3 and Bax, together with increased B-cell lymphoma-2 (Bcl-2) and p-Akt/total Akt ratio. These benefits on ROS and apoptosis attenuation led to improved renal function [23]. Similarly, sulforaphane was shown to exert CIN protection in rats via the Nrf-2/HO-1 pathway, resulting in reduced renal damage and improved Cr [27].…”

“…Resveratrol was shown to attenuate CIN in rats via MYPT-1, myosin-phosphatase target unit; NF-kB, nuclear factor-kB; NQO1, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1; Nrf-2/HO-1, nuclear factor erythroid 2-related factor 2/heme oxygenase 1; PGC-1, peroxisome proliferator-activated receptor gamma-assisted activating factor-1; ROCK, rho-kinase; ROS, reactive oxygen species; SIRT1, silent information regulator 1 increasing SIRT1, PGC-1α, and SOD2, and decreasing phosphorylation of Ser 256 FoxO1 expression, leading to a reduction in oxidative stress, apoptosis, improving renal function [21]. Fasudil, a Rho kinase inhibitor, was shown to decrease ROS and increase SOD-1, and reduced Inflammation via the reduction of NF-kB p65, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [23]. Moreover, apoptosis was decreased via a reduction in cleaved caspase-3 and Bax, together with increased B-cell lymphoma-2 (Bcl-2) and p-Akt/total Akt ratio.…”

Connexin-Based Channels and RhoA/ROCK Pathway in Angiotensin II-Induced Kidney Damage

“…The RhoA/ROCK pathway plays an important role in renal pathophysiology, where RhoA/ROCK participates in the regulation of pro-inflammatory cytokines (e.g., TNF-α and IL-1β) [24,29] and increases the amount of TGF-β and NFκB [27]. On the other hand, great interest has been generated in the use of fasudil, a selective ROCK inhibitor, as regulator in a wide variety of animal models of kidney damage, including unilateral ureteral obstruction, hypertensive glomerulosclerosis, acute renal failure induced by ischemia-reperfusion or by contrast-induced acute kidney injury, and renal failure induced by AngII [27,30]. Fasudil, a ROCK inhibitor, prevents kidney damage by reducing the expression of extracellular matrix genes, OS, pro-inflammatory cytokines, and macrophage infiltration and inhibiting the cascade of events that leads to these effects.…”

Contrast Induced Acute Kidney Injury and Direct Cytotoxicity of Iodinated Radiocontrast Media on Renal Proximal Tubule Cells

“…ROCK plays an important role in various cellular processes including cell adhesion, migration, proliferation, cytokine activation, inflammatory cell migration, smooth muscle cell contraction, and cell cycle regulation. Inhibition of Rho-ROCK pathways has been shown to diminish CI-AKI in vivo (Su et al, 2014;Wang et al, 2018); however, the relationship between CI-AKI and ROCK has not been explored in vitro. The role of the JAK-STAT pathway was determined in a study performed by Yokomaku et al (2008).…”