2. Academic Validation
  3. (Pro)renin receptor mediates tubular epithelial cell pyroptosis in diabetic kidney disease via DPP4-JNK pathway

(Pro)renin receptor mediates tubular epithelial cell pyroptosis in diabetic kidney disease via DPP4-JNK pathway

  • J Transl Med. 2024 Jan 5;22(1):26. doi: 10.1186/s12967-023-04846-5.
Shiying Xie # 1 2,  Shicong Song # 1 2,  Sirui Liu 1 2,  Qiong Li 1 2,  Wei Zou 1 2,  Jianting Ke 1 2,  Cheng Wang 3 4
Affiliations

Affiliations

  • 1 Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.
  • 2 Guangdong Provincial Engineering Research Center of Molecular Imaging Center, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.
  • 3 Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China. [email protected].
  • 4 Guangdong Provincial Engineering Research Center of Molecular Imaging Center, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 38183100 DOI: 10.1186/s12967-023-04846-5
Abstract

Background: (Pro)Renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown.

Methods: In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell Pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell Pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to Dipeptidyl Peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining.

Results: Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells Pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells Pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 Pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death.

Conclusions: This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell Pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD.

Keywords

(Pro)renin receptor; Diabetic kidney disease; Dipeptidyl peptidase 4; Renal tubular cell pyroptosis.

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