Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.

Endothelial cell-derived angiopoietin-like protein 2 supports hematopoietic stem cell activities in bone marrow niches

“…We then measured the mRNA expression of these potential candidates in HSCs purified from Angptl2 fl/fl and Cdh5-Cre;Angptl2 fl/fl or Tie2-Cre;Angptl2 fl/fl mice and demonstrated that G0s2 was markedly decreased in both cKO mice (Figure 4A and Figure S4E). It has been reported that G0S2 is a multifaceted protein with disparate roles in proliferation, metabolism, inflammation and carcinogenesis [42][43][44] . G0s2 also regulates the cell cycle by either suspending cells in G0 phase or enhancing the G1-S switch under different physiological conditions 45 .…”

Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis

“…In contrast to these previous reports, we found that heart failure in 5/6Nx mice was associated with the continuous increase in the expression levels of Clock and Arntl in circulating monocytes. As 5/6Nx-induced renal inflammation was alleviated in Clk / Clk mice 24 , CLOCK protein may promote the CKD-induced inflammatory response. The difference between previous studies and ours suggests that maintenance of normal Clock gene function is important to prevent the onset of heart failure.…”

“…Higher expression levels of STRA6 are observed in the brain, kidneys, spleen, testes, and female genital tract 76 . Indeed, increased expression of CLOCK protein is also detected in the kidneys but not in the liver of 5/6Nx mice 24 , 26 . Therefore, retinol-induced expression of CLOCK protein may be dependent on the levels of STRA6.…”

“…In characterizing the hepatic metabolic status and inflammatory response of wild-type mice with 5/6 nephrectomy (5/6Nx), an experimental model of CKD characterized by the slow development of glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis, and renal inflammation, we found that the abnormal increase in serum retinol levels in 5/6Nx wild-type mice induces the activation of caspase and apoptotic cell death in the kidney, further exacerbating the pathologies of CKD 26 . In contrast, 5/6Nx-induced renal inflammation and apoptotic cell death were attenuated in Clk/Clk mice 24 , despite exhibiting high serum levels of retinol and retinol binding protein 4 (RBP4). Although abnormal retinoid homeostasis is often observed in patients with CKD 27 , it remains unknown whether CKD-induced increase in retinol levels exacerbates cardiovascular disorders via alteration of Clock gene expression.…”

“…Many previous studies report the pathological states of Clk/Clk mice 15 , 22 , 23 . We and others investigated how the mutation of Clock gene affects the pathology of CKD 24 , 25 . In characterizing the hepatic metabolic status and inflammatory response of wild-type mice with 5/6 nephrectomy (5/6Nx), an experimental model of CKD characterized by the slow development of glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis, and renal inflammation, we found that the abnormal increase in serum retinol levels in 5/6Nx wild-type mice induces the activation of caspase and apoptotic cell death in the kidney, further exacerbating the pathologies of CKD 26 .…”