Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Abstract

In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

NF-κB-dependent increase in tissue factor expression is responsible for hypoxic podocyte injury

“…HIF is a key transcription factor which regulates adaptive responses to hypoxia. They demonstrated that the HIF target gene, chemokine receptor C-X-C motif receptor (CXCR4), 4 was prominently increased in podocytes, and HIF-1α showed nuclear localization, which was indicative of HIF activation [10]. Ding et al also showed that forced HIF stabilization by deletion of the Von Hippel-Lindau gene induced CXCR4 in the glomeruli and resulted in necrotizing crescentic glomerulonephritis [11].…”

Tet3-Mediated Hydroxymethylation of Epigenetically Silenced Genes Contributes to Bone Morphogenic Protein 7-Induced Reversal of Kidney Fibrosis

“…nephromine.org). 12,13,23,24 Effective BMP7 treatment of UUO and DN mice (decreased fibrosis) correlated with normalization of Tet3 expression levels ( Figure 1K). In summary, fibrosis was associated with Rasal1 promoter hypermethylation, suppressed Rasal1 expression, and suppressed Tet3 expression (expression of Tet1 and Tet2 were not substantially altered), whereas amelioration of fibrosis was associated with normalization of Rasal1 promoter methylation and Rasal1 expression, de novo hydroxymethylation of Rasal1 promoter, and increased Tet3 expression (Tet1 and Tet2 expression levels were not increased).…”

“…In this regard, transcriptome analysis data on larger cohorts available through the Nephromine database (www.nephromine.org) reveal that CKD caused by minimal change nephropathy and hypertensive nephrosclerosis correlated with decreased RASAL1 expression. [11][12][13] In summary, our results suggest that RASAL1 is hypermethylated in kidney fibrosis, irrespective of the underlying cause, and based on our data, testing the use of RASAL1 methylation as a biomarker of CKD in larger cohorts of patients may deserve consideration.…”

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

“…Increasing evidence indicates that excessive reactive oxygen species (ROS) induced by chronic hyperglycaemia play a central role in the development of diabetic complications [1][2][3]. ROS can activate several proinflammatory transcriptional factors, resulting in the production of cytokines, chemokines and adhesion molecules, as well as an influx of inflammatory cells into the kidney [4,5]. The importance of redox balance in diabetic nephropathy has been demonstrated in diabetic mice overexpressing antioxidant enzymes; these animals are protected from interstitial fibrosis and their proximal tubule cells do not undergo apoptosis [6][7][8][9].…”