Treatment of diabetic kidney disease: current and future targets

DPP-4 inhibitors

DPP-4 inhibitors have been widely used since 2006 to treat patients with type 2 diabetes; nine different drugs are licensed in Korea. They inhibit the DPP-4 enzyme, increasing the level of endogenous plasma glucagon-like peptide-1, which promotes insulin secretion but inhibits glucagon secretion; thereby, lowering the blood glucose level. DPP-4 also cleaves substrates such as neuropeptide Y, high-mobility group protein B1, and meprin-β [8,21]. Recent studies suggest that DPP-4 inhibition is associated with pleiotropic effects on cardiorenal protection. Apart from the glucose-lowering effect, the inhibitors exert anti-oxidant, anti-inflammatory, and anti-fibrotic effects [18,21]. DPP-4 is expressed in most organs and cell types, but the activity levels are tissue-dependent. DPP-4 is expressed at relatively high concentrations in the kidney, especially in the brush borders of proximal tubular cells [22,23]. Some studies have found that DPP-4 expression increased in pathological conditions such as diabetic nephropathy [24-26]. Numerous preclinical and clinical studies now support the notion that DPP-4 exerts a renoprotective effect [24,27-38]; the studies are summarized in Table 1.

Table 1.

Preclinical studies of renoprotection by DPP-4 and SGLT2 inhibitors

In an animal model of type 2 diabetes, sitagliptin ameliorated diabetic nephropathy at the histological level, exerting anti-oxidant and anti-inflammatory effects [24,27,28]. In a mouse model of type 1 diabetes, DPP-4 inhibitors reduced the extent of albuminuria and attenuated renal fibrosis [29-33]. These studies suggest, therefore, that DPP-4 inhibitors exert renoprotective effects via anti-oxidant and anti-inflammatory mechanisms, and by suppressing transforming growth factor (TGF)-mediated signaling. However, further studies are required.

We also observed, in clinical studies, that DPP-4 inhibition exerted a beneficial effect on the kidney. In a small study, sitagliptin significantly reduced albuminuria without lowering the estimated GFR (eGFR) [34], and alogliptin ameliorated albuminuria in patients with type 2 diabetes by upregulating stromal cell-derived factor-1α and reducing oxidative stress [35]. Two other recent clinical studies also reported reduced albuminuria in patients at the end of treatment [36,37], but did not completely exclude the possibility that this was attributable to the glucose-lowering effect of DPP-4 inhibition. However, preclinical data showing that DPP-4 inhibition exerted a renoprotective effect, independently of the glucose-lowering action, have been corroborated in later clinical studies. Groop et al. [38] reported that linagliptin treatment, coupled with stable inhibition of the renal-angiotensin-aldosterone system, significantly reduced albuminuria in patients with diabetes, and that this was not attributable to a reduced blood glucose level or a lowering of blood pressure (BP) [36]. Additional clinical trials have been completed recently (NCT01792518) or are ongoing (NCT01897532); these trials explore the renal effects of DPP-4 inhibitors using outcome measurements including albuminuria and the eGFR. The studies will provide more information on the effects of DPP-4 inhibition on DKD.

SGLT2 inhibitors

SGLT2 inhibitors are oral hypoglycemic agents that reduce renal glucose re-absorption; thereby, increasing urinary glucose excretion, reducing hyperglycemia. These drugs also lower BP and reduce body weight [39]. A recent study found that empagliflozin retarded the development of kidney disease [40]. The cited work also explored the effects of empagliflozin on microvascular outcomes, especially kidney disease progression, in patients enrolled in a randomized, placebo-controlled cardiovascular outcome trial (EMPA-REG OUTCOME [Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients]). The empagliflozin-treated group exhibited a 39% reduction (compared with placebo) in a composite outcome (de novo or worsening nephropathy, or cardiovascular death). In addition, both the number of patients progressing to macroalbuminuria and those exhibiting a doubling of the serum creatinine level were lower in the empagliflozin-treated group than the placebo group [40].

BP and obesity are also risk factors for DKD [7]; thus, reductions in BP and/or body weight may be beneficial. Inhibition of SGLT2 may trigger such effects. SGLT2 inhibitors prevent the development of glomerular hyperfiltration, an early sign of DKD [41,42]. In addition, any drug-mediated effects on (for example) arterial stiffness and/or vascular resistance would reduce the BP [43]; lowered serum uric acid levels may also retard renal disease progression [20,40]. Currently, the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial is evaluating the effects of canagliflozin on renal and vascular outcomes in patients with type 2 diabetes and stage 2 or 3 CKD accompanied by macroalbuminuria (trial code NCT0206579).

Mineralocorticoid receptor antagonists

Aldosterone activates the mineralocorticoid receptor to regulate the sodium balance, but also promotes inflammation and fibrosis [50]. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone increase the risk of hyperkalemia in patients with diabetes and CKD [51]. Patients with CKD and heart failure treated with the non-steroidal MRA finerenone (BAY 94-8862) exhibited reduced albuminuria, which was associated with a lower risk of hyperkalemia than was spironolactone [52]. In addition, a phase II clinical trial explored the utility of finerenone in patients with diabetic nephropathy who were also receiving an ARB or an ACE inhibitor. In such patients, finerenone reduced albuminuria in a dose-dependent manner; however, 1.8% of patients receiving the drug, but none in the placebo group, developed hyperkalemia; no other adverse effect differed in prevalence between the groups [53]. The drug is now in an ongoing phase III trial (code NCT02540993).

Endothelin receptor antagonists

Endothelin 1 (ET-1) is a powerful vasoconstrictor and mitogenic factor exhibiting vasoactive, inflammatory, and profibrogenic properties, and is implicated in cardiovascular and CKD. ET-1 contributes to renal fibrosis via various mechanisms, promoting the accumulation of extracellular matrix components and endothelial cell proliferation, stimulating the epithelial-mesenchymal transition, and upregulating the production of cytokines and growth factors [54]. In a phase III clinical trial, an ET receptor antagonist, avosentan, reduced albuminuria. However, the trial was terminated prematurely because the drug significantly increased fluid overload and the incidence of congestive heart failure. Such adverse effects may be attributable to a natriuretic effect of ET_B receptor inhibition [55]. A clinical trial of the highly selective ET_A receptor antagonist, atrasentan, is ongoing (code NCT01858532).

Apart from these drugs, further materials targeting additional mechanisms linked to DKD progression, such as oxidative stress and uric acid metabolism, are under development [56].

Autophagy

Autophagy is the process by which mammalian cells degrade their own macromolecules and organelles to maintain intracellular homeostasis, and it protects organisms against diverse pathologies, including infections, cancers, neurodegeneration, aging, and heart disease [57]. Recently, autophagy has been implicated in the pathology of a number of diseases, including cancer and diabetes [58,59]. However, accumulating evidence suggests that autophagy plays a cytoprotective role in the kidney [60,61]. Renal autophagy is activated under certain stress conditions, including oxidative stress and hypoxia, and in kidneys of diabetic animal models, but is suppressed in obese patients with type 2 diabetes [62,63]. Autophagy has been observed both in podocytes and proximal tubular cells, but plays contrasting roles in these cell types. Podocytes require a basal level of autophagy to maintain cellular homeostasis, whereas proximal tubular cells use autophagy as a coping mechanism when nephrotoxic stress is in play. Therefore, if a treatment for diabetic nephropathy were to seek to regulate autophagy, the specificity of such treatment might be problematic [60].

Src family kinases

The Src family kinases (SFKs) are non-receptor tyrosine kinases activated by autophosphorylation of their Tyr416 residues, and are induced by certain cytokines and growth factors including TGF-β1 and epidermal growth factor [64]. The SFKs include Src, Fyn, Yes, Yrk, Blk, Fgr, Hck, Lck, Lyn, and the Frk subfamily proteins [65]; all contain a unique amino-terminal region, two Src homology domains (SH2 and SH3), highly conserved kinase domains, and carboxy-terminal tails containing the (negatively) regulatory tyrosine residue [66]. Src, Fyn, and Yes are expressed in most tissues, but their activities are tissue-dependent; the other SFKs are typically expressed in hematopoietic cells [65]. SFKs dysregulate many cellular processes, including invasion, migration, proliferation, angiogenesis, and apoptosis, and have been targeted principally in efforts to treat various types of cancer [66].

Recent studies have suggested that the Src is a potential target when it is sought to treat kidney fibrosis. High glucose levels activate the Src of mesangial cells and the glomeruli of rats with streptozotocin (STZ)-induced diabetes [67,68]. Taniguchi et al. [68] reported that pharmacological inhibition of Sfc by PP2 and SU6656 blocked high-glucose-stimulated Sfc phosphorylation (at Tyr-416), the EGF receptor (EGFR), mitogen-activated protein kinase, and the tumor necrosis factor α-converting enzyme. Moreover, diabetic STZ-treated mice treated with PP2 exhibited reduced albuminuria, less glomerular collagen accumulation, and reduced podocyte loss, attributable to inhibition of EGFR phosphorylation [68]. Yan et al. [69] reported that PP1-mediated inhibition of the Src kinase reduced fibrosis in either the presence or absence of TGF-β stimulation in vitro, and attenuated renal interstitial fibrosis after the development of unilateral ureteral obstruction in vivo. These renoprotective effects were mediated by suppression of TGF-β signaling, reduced phosphorylation of both EGFR and the signal transducer and activator of transcription-3 (STAT-3), and cell-cycle arrest [69]. Src inhibitors are currently being developed for cancer patients; various treatments are being evaluated in phase 0-to-phase III clinical trials [66]. As SRC inhibition reduces renal fibrosis, Zhou and Liu [70] have proposed that such an effect could translate into effective remedies for patients with kidney disease. Apart from the Src effects, we recently showed that Fyn, another SFK, was activated in animals with unilateral ureteral obstruction-induced renal fibrosis, and that Fyn inhibition attenuated fibrosis by downregulating STAT-3 [71]. Together, the results suggest that SFK may be a valuable therapeutic target in patients with renal fibrosis.