Nox2 and Cyclosporine-Induced Renal Hypoxia

Abstract

Background We hypothesized that Nox2 plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. Methods We tested this hypothesis in Fisher 344 rats, C57BL/6J wild type and Nox2−/− mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (BOLD and DCE MRI) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. Results We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (BOLD and DCE MRI, pimonidazole, HIF1-α). Nox2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, HNE), and fibrogenesis (α-SMA, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury-repair, metabolism, and oxidative stress in Nox2−/− mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-SMA and picrosirius levels compared to controls. Conclusions These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α, and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic CNI nephrotoxicity.

PEGylated pUR4/FUD peptide inhibitor of fibronectin fibrillogenesis decreases fibrosis in murine Unilateral Ureteral Obstruction model of kidney disease

“…However, because the contralateral kidney remains intact in the UUO model, renal function is not affected [ 57 ]. Therefore, whether PEG-FUD improves renal function will necessitate future testing in a kidney disease model that affects both kidneys, such as the ischemia reperfusion injury, subtotal 5/6 nephrectomy [ 57 , 58 ], or chronic allograft nephropathy [ 59 ].…”

Cyclosporine A induces endothelin‐converting enzyme‐1: Studies in vivo and in vitro

“…Hypoxia conceivably plays a pivotal role in CsA nephropathy. Altered microcirculation and medullary hypoxia develop as evidenced with by unenhanced MRI techniques and regional HIF expression, as well as with pimonidazole (PIM) immunostaining . Enhanced sympathetic activity and release of thromboxane, coupled with altered prostacyclin and nitric oxide production, have all been implicated as potential causes of CsA‐induced renal vasoconstriction, hypoxia and impaired GFR .…”

“…Enhanced sympathetic activity and release of thromboxane, coupled with altered prostacyclin and nitric oxide production, have all been implicated as potential causes of CsA‐induced renal vasoconstriction, hypoxia and impaired GFR . Likewise, free radical formation by NADPH oxidase also impairs microcirculation, promoting hypoxia . The renin‐angiotensin‐aldosterone axis also plays a role in the generation of interstitial fibrosis, likely with the induction of hypoxia .…”

Chenodeoxycholic acid alleviated the cyclosporine-induced nephrotoxicity by decreasing oxidative stress and suppressing renin-angiotensin system through AT2R and ACE2 mRNA upregulation in rats

“…On the other hand, it has been reported that NADPH oxidase 4 (NOX4) is the NOX isoform with the highest expression in the kidney, while NOX1 and NOX2 are expressed at a lower levels and play an important role in CsA-induced oxidative stress(Rajaram et al 2019). Indeed, renal NOX4 and NOX2 mRNA/protein expressions were upregulated in CsA-rodents(Djamali et al 2016;Tan et al 2020, Bekpınar et al 2019Kalaycı et al 2023). In our study, renal NOX4 and NOX2 expressions were also upregulated in CsA-rats, and these expressions decreased due to CDCA, but did not return to normal levels.Moreover, in our study, renal NF-κB, TNF-α and IL-6 levels, and MPO activity were detected to elevate in CsA rodents as previously reported (El-Kashef et al 2018;Harb et al 2021; Nouri et al 2022), but CDCA treatment decreased TNF-α level but not MPO activity.…”