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Published on: November 7, 2017
Role of Nox4 in murine models of kidney disease
Andrea Babelova1, Despina Avaniadi, Oliver Jung
1Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt am Main, Germany.
Abstract:
Nox4 is a hydrogen peroxide-producing NADPH oxidase highly expressed in the kidney which has been linked to epithelial cell injury and diabetic-induced cellular dysfunction in cultured cells. The role of the enzyme for renal pathology in vivo, however, is unclear. To address this, three experimental animal models of renal injury (streptozotocin diabetes I, unilateral ureteral ligation (UUO), and 5/6 nephrectomy (5/6Nx)) were studied in either Nox4-inducible (Nox4(*/*)) or constitutive knockout (Nox4(-/-)) mice. Nox4 contributed more than 80% of diphenylene iodonium-sensitive H(2)O(2) formation of freshly isolated tubules determined by Amplex Red assay. In streptozotocin diabetes, acute deletion of Nox4 by tamoxifen-activated cre-recombinase increased albuminuria, whereas matrix deposition was similar between WT and Nox4(*/*) mice. Interestingly, renal Nox4 expression, mainly localized to tubular cells, decreased in the course of diabetes and this was not associated with a compensatory upregulation of Nox1 or Nox2. In the UUO model, renal expression of ICAM1, connective tissue growth factor, and fibronectin were higher in kidneys of Nox4(*/*) than control mice. Also in this model, levels of Nox4 decreased in the course of the disease. In the 5/6Nx model, which was performed in SV129 and SV129-Nox4(-/-) mice, no difference in the development of hypertension and albuminuria was found between the strains. Collectively, the first in vivo data of the kidney do not support the view that Nox4 is a main driver of renal disease. It rather appears that under specific conditions Nox4 may even slightly limit injury and disease progression.
Insights
Nox4 (NADPH oxidase 4) does not drive kidney disease in vivo. Studies in mouse models suggest Nox4 may limit injury and disease progression under certain conditions, contrary to prior cell culture findings.
Area of Science:
- Nephrology
- Biochemistry
- Molecular Biology
Background:
- Nox4, a major hydrogen peroxide producer in the kidney, is implicated in epithelial cell injury and diabetic dysfunction in cell cultures.
- Its specific role in in vivo renal pathology remains largely undetermined.
Purpose of the Study:
- To investigate the in vivo role of Nox4 in three distinct models of experimental kidney injury.
- To determine if Nox4 acts as a driver of renal pathology or offers protective effects.
Main Methods:
- Utilized Nox4-inducible and constitutive knockout mouse models.
- Examined streptozotocin-induced diabetes, unilateral ureteral ligation (UUO), and 5/6 nephrectomy (5/6Nx) models.
- Quantified hydrogen peroxide production, albuminuria, matrix deposition, and inflammatory markers.
Main Results:
- Nox4 deletion exacerbated albuminuria in diabetic mice but did not alter matrix deposition.
- Unilateral ureteral ligation in Nox4 knockout mice showed increased ICAM1, CTGF, and fibronectin.
- No significant differences in hypertension or albuminuria were observed in the 5/6Nx model between strains.
- Renal Nox4 expression decreased during disease progression in diabetes and UUO models.
Conclusions:
- In vivo data do not support Nox4 as a primary driver of kidney disease.
- Nox4 may exert a protective role, potentially limiting injury and disease progression in specific renal injury contexts.
