Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

Diabetic nephropathy (DN) not only is a major cause of end-stage renal disease (ESRD) in developing and developed countries but also plays a critical role as a risk factor for cardiovascular disease. The pathogenesis of DN is multifactorial and remains to be elucidated. It is well known that dyslipidemia is frequently complicated with diabetes. Recently, dyslipidemia has been recognized to be involved in the progression of DN. In general, diabetic dyslipidemia is caused by impaired action of lipoprotein lipase (LPL) that is localized to the endothelial cells, resulting in increased serum levels of increased triglyceride (TG) and decreased high-density lipoprotein cholesterol (HDL-C). Smaller size and modified low-density lipoprotein (LDL), such as glycated and oxidized LDL, play important roles to induce vascular and renal cellular dysfunction. Previous studies demonstrated that dyslipidemia enhances macrophage infiltration and excessive extracellular matrix (ECM) production in the glomeruli under diabetic conditions, leading to the development of DN. Clinical studies have demonstrated that lipid-lowering therapy shows a protective effect on the renal function. It is well known that statins reduce albuminuria in patients with DN. A series of our studies indicated that this effect is mediated by Rho-kinase inhibition. Rho-kinase plays a key role in the pathogenesis of DN by activating the inflammatory pathway, including oxidative stress, NF-κB, and hypoxia inducible factor (HIF)-1. Intriguingly, Rho-kinase inhibitors have been shown to attenuate glomerulosclerosis as well as atherosclerosis. Therefore, Rho-kinase could be a promising therapeutic target for both DN and cardiovascular disease.

The small GTPase Rho and its effector Rho-kinase are involved in the pathogenesis of diabetic nephropathy. Accumulating evidence shows that hypoxia-inducible factor-1α (HIF-1α) is a key regulator of renal sclerosis under diabetic conditions. However, the interactions of Rho-kinase and HIF-1α in the development of renal dysfunction have not been defined. Here, we assessed whether Rho-kinase blockade attenuates HIF-1α induction and the subsequent fibrotic response using type 2 diabetic mice and cultured mesangial cells. Fasudil, a Rho-kinase inhibitor, reduced urinary albumin excretion, mesangial matrix expansion, and the expression of fibrotic mediators in db/db mice. Mechanistically, HIF-1α accumulation and the expression of its target genes that contribute to diabetic glomerulosclerosis were also prevented by fasudil in the renal cortex. In mesangial cells, Rho/Rho-kinase signaling was activated under hypoxic conditions. Further in vitro studies showed that pharmacological and genetic inhibition of Rho-kinase promoted proteasomal HIF-1α degradation, which subsequently suppressed HIF-1-dependent profibrotic gene expression by upregulation of prolyl hydroxylase 2. Thus, we found a previously unrecognized renoprotective mechanism for the effects of Rho-kinase inhibition and this could be a potential therapeutic target for the treatment of diabetic nephropathy.

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The small GTPase Rho and its downstream effector, Rho-associated coiled-coil containing protein kinase (Rho-kinase), regulate a number of cellular processes, including organization of the actin cytoskeleton, cell adhesion, and migration. While pharmacological inhibitors of Rhokinase signaling are known to block renal inflammation, the molecular basis for this effect is unclear. Here, we provide evidence that proinflammatory TNF-␣ promotes mesangial expression of macrophage colony-stimulating factor (M-CSF), a key regulator for the growth and differentiation of mononuclear phagocytes, in a Rhokinase-dependent manner. Consistent with this observation, TNF-␣-mediated renal expression of M-CSF in insulin-resistant db/db mice was downregulated by Rho-kinase inhibition. Small interfering RNAfacilitated knockdown of Rho-kinase isoforms ROCK1 and ROCK2 indicated that both isoforms make comparable contributions to regulation of M-CSF expression in mesangial cells. From a mechanistic standpoint, Western blotting and EMSA showed that Rho-kinase and its downstream target p38 MAPK regulate nuclear translocation of NF-B RelA/p65 and subsequent DNA binding activity, with no significant effects on IB␣ degradation and RelA/p65 phosphorylation. Moreover, we showed that Rho-kinase-mediated cytoskeletal organization is required for the nuclear uptake of RelA/p65. Collectively, these findings identify Rho-kinase as a critical regulator of chemokine expression and macrophage proliferation.

Diabetes is a worldwide health issue closely associated with cardiovascular events. Given the pandemic of obesity, the identification of the basic underpinnings of vascular disease is strongly needed. Emerging evidence has suggested that endothelial dysfunction is a critical step in the progression of atherosclerosis. However, how diabetes affects the endothelium is poorly understood. Experimental and clinical studies have illuminated the tight link between insulin resistance and endothelial dysfunction. In addition, macrophage polarization from M2 towards M1 contributes to the process of endothelial damage. The possibility that novel classes of anti-hyperglycemic agents exert beneficial effects on the endothelial function and macrophage polarization has been raised. In this review, we discuss the current status of knowledge regarding the pathological significance of insulin signaling in endothelium. Finally, we summarize recent therapeutic strategies against endothelial dysfunction with an emphasis on macrophage polarity.

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db/ db mice demonstrated increased gene expression of transforming growth factor (TGF)-β and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db/ db mice was elevated compared with control db/ m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db/ db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.