KLF6 Acetylation Promotes Sublytic C5b-9-Induced Production of MCP-1 and RANTES in Experimental Mesangial Proliferative Glomerulonephritis

Abstract

Rat Thy-1 nephritis (Thy-1N) is an experimental mesangial proliferative glomerulonephritis (MsPGN) for studying human MsPGN. Although sublytic C5b-9 complex formation on glomerular mesangial cells (GMCs) and renal MCP-1 and RANTES production in rats with Thy-1N have been proved, the role and mechanism of MCP-1 or RANTES synthesis in GMCs induced by sublytic C5b-9 are poorly elucidated. In this study, we first found the expression of transcription factor (KLF6), co-activator (KAT7) and chemokines (MCP-1 and RANTES) was all up-regulated both in renal tissue of Thy-1N rats (in vivo) and in sublytic C5b-9-induced GMCs (in vitro). Further in vitro experiments revealed that KLF6 bound to MCP-1 promoter (-297 to-123 nt) and RANTES promoter (-343 to-191 nt), leading to MCP-1 and RANTES gene transcription. Meanwhile, KAT7 also bound to the same region of MCP-1 and RANTES promoter in a KLF6-dependent manner, and KLF6 was acetylated by KAT7 at lysine residue 100, which finally promoted MCP-1 and RANTES expression. Moreover, our in vivo experiments discovered that knockdown of renal KAT7 or KLF6 gene obviously reduced MCP-1 and RANTES production, GMCs proliferation, ECM accumulation, and proteinuria secretion in Thy-1N rats. Collectively, our study indicates that sublytic C5b-9-induced MCP-1 and RANTES synthesis is associated with KAT7-mediated KLF6 acetylation and elevated KLF6 transcriptional activity, which might provide a new insight into the pathogenesis of rat Thy-1N and human MsPGN.

Single-Cell Profiling Reveals Transcriptional Signatures and Cell-Cell Crosstalk in Anti-PLA2R Positive Idiopathic Membranous Nephropathy Patients

“…The more specific information of DEGs from various kidney cells in two groups of IMN was shown in Dataset 5. ECs, MCs, PTs, LOHs, DTs, as well as ICs in IMN patients with massive proteinuria had elevated expression of KLF6 that might participate in the glomerular mesangial cell proliferation, ECM accumulation, and proteinuria secretion (38). All the intrinsic kidney cells except for podocytes, pericytes, fibroblasts, and epithelial cells in IMN patients with massive proteinuria highly expressed SOCS3, a cytokine-inducible protein that might contribute to the regulation of receptor signaling in immune complex glomerulonephritis, in parallel with proteinuria and kidney lesions (39).…”

Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology

“…In addition to its role as the mediator of diabetic-associated complications, KLF6 has also been implicated in promoting the pathogenesis of mesangial proliferation glomerulonephritis (MsPGN). It has been demonstrated that the lysine acetyltransferase 7 (KAT7)-mediated acetylation of KLF6 directly transactivated the expression of chemokines MCP1 and RANTES, subsequently leading to the proliferation and inflammation of glomerular mesangial cells, extracellular matrix accumulation and development of proteinuria [ 139 ].…”

Modulation of IL-6 Expression by KLF4-Mediated Transactivation and PCAF-Mediated Acetylation in Sublytic C5b-9-Induced Rat Glomerular Mesangial Cells

“…Previous studies have demonstrated that renal pathologic changes in Thy-1N rats are complement-dependent, especially sublytic C5b-9-dependent (7)(8)(9)(10). In the early stage of Thy-1N, a number of proinflammatory cytokines are produced by GMCs in response to sublytic C5b-9 stimulus (8)(9)(10).…”

“…Thy-1 nephritis (Thy-1N) as a popular experimental model for MsPGN is induced in the rat by injection of antibody to Thy-1, triggering activation of the complement system and subsequent formation of C5b-9 on the surface of GMC membranes (4)(5)(6). Previous studies have demonstrated that renal pathologic changes in Thy-1N rats are complement-dependent, especially sublytic C5b-9-dependent (7)(8)(9)(10). In the early stage of Thy-1N, a number of proinflammatory cytokines are produced by GMCs in response to sublytic C5b-9 stimulus (8)(9)(10).…”