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

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.

In situ Metabolomics of Metabolic Reprogramming Involved in a Mouse Model of Type 2 Diabetic Kidney Disease

“…As predicted, db/db mice showed a higher mRNA expression of SAT1 in both the renal cortex and medulla, and also a stronger level of SAT1 expression in situ compared with db/m mice. These findings suggest a potential role of SAT1 in the development of type 2 DKD, as reported in a previous study ( Zhang et al, 2021 ).…”

“…In mammals, arginine can be catalyzed to polyamines, including putrescine, spermidine, and spermine. There is growing evidence suggesting that the dysregulation of polyamine metabolism can cause changes in high glucose-induced energy perturbation, including streptozotocin (STZ)-induced diabetic cardiomyopathy ( Wang et al, 2020a ), type 1 DKD ( Zhang et al, 2021 ), and retinopathy ( Liu et al, 2020 ), thus making it a promising target for therapeutic intervention. It has been reported that, as ROS scavengers, spermine and spermidine can protect DNA from free radical attacks, regulating cell proliferation, differentiation, and apoptosis ( Pegg, 2009 ; Wang et al, 2020a ).…”

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

“…However, the reduction in p-AMPK level and the resulting increase in p-mTOR level in HG group did not lead to the inhibition of autophagy, indicating that the high-glucose condition suppressed the activation of AMPK, and the AMPK/mTOR axis was not the critical regulator of autophagy in high-glucose environment without other interventions. Indeed, numerous studies found that high-glucose condition enhanced autophagy while reducing p-AMPK and increasing p-mTOR [ 42 , 52 – 55 ]. In this study, the addition of GW501516 greatly enhanced p-AMPK level, yielding decreased mTOR level, which further increased autophagy.…”

Spermine Regulates Immune and Signal Transduction Dysfunction in Diabetic Cardiomyopathy

“…The experimental mice showed hyperglycemia, hyperinsulinemia, weight loss, and abnormal cardiac function and structure (data not shown). Spermine (SPM) is one of the important products of polyamine metabolism in mammals, which has been proven to have many myocardial protective effects, for example, antifibrosis, inhibition of oxidative stress and endoplasmic reticulum stress, promotion of autophagy, and recovery of energy metabolism (9)(10)(11)(22)(23)(24). However, the effects of immune response and related signal transduction process on the DCM model of C57BL/6J mice, and the regulatory role of SPM, a potential modulator for myocardial injury in DCM, are not clear.…”