Characterization of septin expression in normal and fibrotic kidneys

Abstract

Chronic kidney disease (CKD) is characterized by the loss of nephrons and worsening organ-fibrosis that leads to deterioration and ultimately the total breakdown of kidney function. Renal fibrosis has become a major public health problem worldwide and necessitates hemodialysis and kidney transplantation in affected patients. CKD is mainly characterized by the activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix components, causing the disruption of the normal tissue architecture of the kidney. Septins are GTPase proteins associated with membranes, actin filaments, and microtubules and are undoubtedly crucial for cytoskeleton organization. Although some septins are involved in liver fibrosis, they have not been investigated in the context of renal fibrosis. Here, we show that numerous septins are expressed in the healthy kidney and demonstrate in fibrotic mouse kidneys that various septins are remarkably up-regulated in the tubulointerstitium compared to contralateral control kidneys. We observed the same findings in human fibrotic kidneys. In both healthy and fibrotic kidneys, septins are coexpressed with extracellular matrix components, reinforcing the structural function of septins as cytoskeletal components. Furthermore, we could show in septin 8-deficient mice that septin 8 is dispensable for the formation of renal fibrosis, and that no other septin was compensatory changed in kidneys compared to wild-type mice.

Impaired Platelet Function in Sept8-Deficient Mice In Vitro

“…16 A further indication is that Sept8 is markedly increased in tissues, which undergo remodeling, like kidney fibrosis. 34 Also, after platelet activation, extensive cytoskeletal reorganization with disrupted cell-cell adhesions, cell scattering, and enhancement of cell motility which is critical for granule secretion, can be observed. Sept8 could contribute in this process, because it interacts with actin filaments, microtubules, and intermediate filaments.…”

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

“…Septins are a group of GTPase proteins that play a role in cytoskeleton organisation through their links with microtubules and actin filaments (78). Although some septins are associated with the advancement of kidney fibrosis (78), SEPTIN9 specifically has been implicated in a host of disease pathologies, such as prostate cancer (79), colorectal cancer (80), liver fibrosis (81) and T2DM (82).…”

Novel Functions of the Septin Cytoskeleton

“…The only comprehensive characterization of septin expression in fibrotic tissues was performed in a mouse model of kidney fibrosis. 91 A gene expression analysis for different septins (SEPT1 and SEPT4 through SEPT11) demonstrates a significant up-regulation of all septin transcripts in the fibrotic kidney compared with controls. Immunohistologic experiments detect SEPT7 and SEPT8 protein up-regulation primarily in the tubulointerstitial region of the fibrotic kidney.…”

“…Interestingly, septins were shown to significantly colocalize with the myofibroblast marker asmooth muscle actin in the diseased kidneys. 91 SEPT4 and SEPT6 were also found up-regulated in different rodent models of liver fibrosis, where they were associated with hepatic stellate cells (HSC). 90,104 However, given a recent report that shows down-regulation of SEPT9 expression in carbon tetrachlorideeinduced liver fibrosis, septin expression could be a subject of more complex regulation in fibrotic tissues.…”