1. Introduction
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the United States (Reidy, Kang, Hostetter & Susztak, 2014). Although chronic hyperglycemia has been considered as the main culprit for microvascular complications of diabetes, the underlying mechanism of DKD remains poorly understood (Rossello & Yellon, 2017). Current strategies show limited efficacy in preventing the progression of DKD, such as control of blood pressure and glucose levels along with administration of angiotensin-receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEI) (Gregg et al., 2014). These findings remind us that there may be some unknown mechanisms that involved in the development of DKD.
Emerging evidence has showed that the proximal tubule plays a pivotal role in the initiation and progression of DKD (Russo, Sandoval, Campos, Molitoris, Comper & Brown, 2009). The kidney, especially the proximal tubules is high-energy demanded and rich of mitochondria (Weinberg, Venkatachalam, Roeser & Nissim, 2000). Recent studies have confirmed the involvement of mitochondria fission in the development of DKD (Bhargava & Schnellmann, 2017). As a result of loss of mitochondrial membrane potential, fission is induced by the translocation of dynamin-related protein 1 (DRP1) from the cytosol to the mitochondrial outer membrane (Bhargava & Schnellmann, 2017). Bunch of studies have suggested the posttranscriptional phosphorylation of Drp1 as a key modulator of mitochondrial fission. Phosphorylation at Serine-616 is associated with increased activity of DRP1 (pro-fission). On the contrary, phosphorylation at Serine-637 shows opposite effect (anti-fission) (Chang & Blackstone, 2007). However, the underlying molecular mechanism for mitochondrial dynamics regulation in DN are not fully understood.
Recent studies showed that metformin and 5-aminoimidazole-4- carboxamide-1-riboside (AICAR) could attenuate DKD in vitro and in vivo experiments by activating Adenosine 5’-monophosphate activated protein kinase-(AMPK) (Lee et al., 2013; Takiyama et al., 2011). Meanwhile, AMPK was reported as a regulator of mitochondrial homeostasis via inhibiting mitochondrial fission in several studies (Toyama et al., 2016; Wang et al., 2017). So, we hypothesize that the renal protective effect of AMPK was correlated with its anti-fission function, but the underling mechanisms remained unclear.
Phosphoglycerate mutase family member 5 (PGAM5) plays an important role in the initiation of mitochondrial fission by dephosphorylating the DRP1S637 and promoting DRP1 mitochondrial translocation (Wang, Jiang, Chen, Du & Wang, 2012). PGAM5 is a mitochondria-resident protein. Bunch of studies have confirmed its involvement in the development of Parkinson’s disease (Lu et al., 2014), acute kidney injury (Gu et al., 2019) and liver inflammation (Kang et al., 2015). However, whether the PGAM5 participates in the development of DKD and if the AMPK involved in the regulation of PGAM5 in DKD are unknown.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were recently developed as a class of anti-diabetic agents to promote urine glucose excretion without changing the secretion of insulin (Steven et al., 2017; Zinman, Lachin & Inzucchi, 2016). Clinical trials have observed encouraging effect of SGLT2 inhibitors on improving DKD outcomes (Neal, Perkovic & Matthews, 2017; Perkovic et al., 2019; Wanner, Inzucchi & Zinman, 2016), though the underlining mechanisms are remained controversial. Recent evidence showed that the SGLT2 inhibitors, Empagliflozin (Empa), can activate AMPK and alleviate the mitochondrial fission in diabetic myocardial microvascular endothelial cell through recovering the decreased phosphorylation of DRP1 at the Serine-637 (Zhou, Wang, Zhu, Hu, Chen & Ren, 2018), suggesting the possible involvement of PGAM5. Since the proximal tubules are the main site of SGLT2 expression and rich of mitochondria (Washburn & Poucher, 2013), we hypothesize that the Empa could fulfill its renal protective effect by alleviating mitochondrial fission via prompting the AMPK phosphorylation in DKD and the PGAM5 may be involved in this procedure.