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<p>Excessive protein intake is one of the main accelerators for chronic kidney disease including diabetic kidney disease (DKD). DKD is known to be a leading cause of end-stage renal disease; however, detailed molecular mechanisms remain unclear. Natriuretic peptides (NPs)/guanylyl cyclase-A (GC-A) signaling has been reported to exert protective effects against aldosterone-induced kidney injury. To investigate the role of NPs/GC-A pathway against DKD progression, we administered streptozotocin to systemic GC-A knockout (KO) mice and endothelial cell-specific GC-A conditional knockout (EC-GC-A cKO) mice, and fed high-protein diet (HPD) for 4&#xa0;weeks. Furthermore, human glomerular endothelial (GE) cells were transfected with siRNA for GC-A and stimulated with high-protein and high-glucose medium. Systemic GC-A KO mice and EC-GC-A cKO mice with HPD showed increased albuminuria with glomerular enlargement, interstitial fibrosis and upregulation of proinflammatory and profibrotic mRNA expression. In systemic GC-A KO mice with HPD, genes related to renin–angiotensin–aldosterone system, including mineralocorticoid receptor (MR) pathway, were also upregulated, and finerenone administration ameliorated diabetes- and HPD-induced kidney injury. GC-A knockdown enhanced <i>TGFB1</i> and <i>SERPINE1</i> mRNA expression in GE cells, and these changes were ameliorated by SGK1 inhibitor. These findings reveal the significance of NPs/GC-A pathway in HPD-induced kidney injury and the effectiveness of MR/SGK1 pathway inhibition.</p>

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Finerenone ameliorates diabetic kidney disease exacerbated by deletion of natriuretic peptide/guanylyl cyclase-A signaling and dietary high-protein load

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Yui Inoue,
  • Akira Ishii,
  • Takuya Ishimura,
  • Hiroyuki Yamada,
  • Sayaka Sugioka,
  • Takaya Handa,
  • Akie Ikushima,
  • Haruomi Nishio,
  • Yukiko Kato,
  • Shoko Ohno,
  • Yasuaki Nakagawa,
  • Koichiro Kuwahara,
  • Taiji Matsusaka,
  • Takeshi Tokudome,
  • Motoko Yanagita,
  • Hideki Yokoi

摘要

Excessive protein intake is one of the main accelerators for chronic kidney disease including diabetic kidney disease (DKD). DKD is known to be a leading cause of end-stage renal disease; however, detailed molecular mechanisms remain unclear. Natriuretic peptides (NPs)/guanylyl cyclase-A (GC-A) signaling has been reported to exert protective effects against aldosterone-induced kidney injury. To investigate the role of NPs/GC-A pathway against DKD progression, we administered streptozotocin to systemic GC-A knockout (KO) mice and endothelial cell-specific GC-A conditional knockout (EC-GC-A cKO) mice, and fed high-protein diet (HPD) for 4 weeks. Furthermore, human glomerular endothelial (GE) cells were transfected with siRNA for GC-A and stimulated with high-protein and high-glucose medium. Systemic GC-A KO mice and EC-GC-A cKO mice with HPD showed increased albuminuria with glomerular enlargement, interstitial fibrosis and upregulation of proinflammatory and profibrotic mRNA expression. In systemic GC-A KO mice with HPD, genes related to renin–angiotensin–aldosterone system, including mineralocorticoid receptor (MR) pathway, were also upregulated, and finerenone administration ameliorated diabetes- and HPD-induced kidney injury. GC-A knockdown enhanced TGFB1 and SERPINE1 mRNA expression in GE cells, and these changes were ameliorated by SGK1 inhibitor. These findings reveal the significance of NPs/GC-A pathway in HPD-induced kidney injury and the effectiveness of MR/SGK1 pathway inhibition.