CNDP2 drives renal tubular fibrosis in diabetic kidney disease via a sulfur-containing amino acids-mTOR signaling axis

  • Biochim Biophys Acta Mol Basis Dis. 2026 Oct;1872(7):168312. doi: 10.1016/j.bbadis.2026.168312.
Yan Li  1 ,  Qiao-An Zheng  2 ,  Yan-Rong Chen  2 ,  Chang Su  3 ,  Jia-Yi Luo  3 ,  Zong-Ji Zheng  3 ,  Jun-Yu Xue  3 ,  Zhuo Wang  4 ,  Yu-Hua Chen  2 ,  Ping Liu  2 ,  Zhong-Qiu Guo  5 ,  Yao-Ming Xue  6
Affiliations
  • 1. Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Endocrinology and Metabolism, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
  • 2. Department of Endocrinology and Metabolism, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
  • 3. Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 4. Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 2001 Longxiang Road, Longgang District, Shenzhen, 518172, China.
  • 5. Department of Endocrinology and Metabolism, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China. Electronic address: [email protected].
  • 6. Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 42276307 DOI: 10.1016/j.bbadis.2026.168312
Abstract

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with proximal tubule fibrosis being a key pathological feature. Our previous study identified significant upregulation of cytosolic nonspecific dipeptidase 2 (CNDP2) in the renal tubules of a DKD mouse model, yet its functional role remains unclear.

Objective: This study aimed to investigate the role of CNDP2 in renal tubular fibrosis during DKD, focusing specifically on the "sulfur-containing Amino acids (SAAs) metabolism-mammalian target of rapamycin (mTOR)" signaling axis.

Methods: We employed integrated in vivo and in vitro models. Kidney- specific Cndp2 knockdown was achieved using an adeno-associated virus vector, and the CNDP2 inhibitor bestatin was used for pharmacological intervention. Renal function, fibrosis, the Ragulator-Rag GTPase-mTOR signaling pathway, amino acid profiles, and ultrastructural changes were assessed. A dietary intervention restricting SAAs was also applied.

Results: CNDP2 was specifically upregulated in renal tubules under DKD conditions. Both genetic knockdown and pharmacological inhibition of CNDP2 significantly improved renal function and attenuated fibrosis. Mechanistically, CNDP2 hydrolyzes dipeptides, leading to elevated levels of SAAs (cysteine/cystine). This promotes the activation of the Ragulator-Ras-related GTPase (Rag) complex, resulting in subsequent hyperactivation of mTOR signaling and driving tubular fibrosis. Notably, dietary restriction of SAAs similarly ameliorated DKD pathology.

Conclusion: CNDP2 drives renal tubular fibrosis in DKD by activating mTOR signaling through disruption of SAAs metabolism. Our findings reveal a novel "CNDP2-SAAs-mTOR" pathway, identifying CNDP2 as a promising therapeutic target for DKD intervention.

Keywords
Cytosolic nonspecific dipeptidase 2; Diabetic kidney disease; Mammalian target of rapamycin; Sulfur-containing amino acids.
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