1. Academic Validation
  2. Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

  • Int J Mol Med. 2021 Mar;47(3):27. doi: 10.3892/ijmm.2021.4860.
Xinying Zhang  # 1 Li Zhang  # 2 Zhe Chen 3 Siwei Li 1 Bingbing Che 1 Ningning Wang 1 Junting Chen 4 Changqing Xu 1 Can Wei 1
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
  • 2 Department of Rehabilitation, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China.
  • 3 Department of Infectious Diseases, General Hospital for The Head Office of Agricultural Cultivation of Heilongjiang, Harbin, Heilongjiang 150088, P.R. China.
  • 4 Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
  • # Contributed equally.
Abstract

Diabetic nephropathy (DN) is the primary cause of end‑stage renal disease, which is closely associated with dysfunction of the podocytes, the main component of the glomerular filtration membrane; however, the exact underlying mechanism is unknown. Polyamines, including spermine, spermidine and putrescine, have antioxidant and anti‑aging properties that are involved in the progression of numerous diseases, but their role in DN has not yet been reported. The present study aimed to explore the role of polyamines in DN, particularly in podocyte injury, and to reveal the molecular mechanism underlying the protective effect of exogenous spermine. Streptozotocin intraperitoneal injection‑induced type 1 diabetic (T1D) rat models and high glucose (HG)‑stimulated podocyte injury models were established. It was found that in T1D rat kidneys and HG‑induced podocytes, ornithine decarboxylase (a key Enzyme for polyamine synthesis) was downregulated, while spermidine/spermine N1‑acetyltransferase (a key Enzyme for polyamines degradation) was upregulated, which suggested that reduction of the polyamine metabolic pool particularly decreased spermine content, is a major factor in DN progression. In addition, hyperglycemia can induce an increased rat kidney weight ratio, serum creatinine, urea, urinary albumin excretion and glomerular cell matrix levels, and promote mesangial thickening and loss or fusion of podocytes. The expression levels of podocyte marker proteins (nephrin, CD2‑associated protein and podocin) and autophagy‑related proteins [Autophagy protein 5, microtube‑associated proteins 1A/1B LIGHT chain 3 (LC3)II/LC3I, Beclin 1 and phosphorylated (p)‑AMPK] were downregulated, while cleaved caspase‑3, p62 and p‑mTOR were increased. These changes could be improved by pretreatment with exogenous spermine or rapamycin (autophagic agonist). In conclusion, spermine may have the potential to prevent diabetic kidney injury in rats by promoting Autophagy via regulating the AMPK/mTOR signaling pathway.

Keywords

diabetic nephropathy; podocyte; spermine; autophagy; AMPK/mTOR pathway.

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