The Wnt Signaling Pathway in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.

Kidney microRNA Expression Pattern in Type 2 Diabetic Nephropathy in BTBR Ob/Ob Mice

“…Hyperglycemia has been considered the driving and triggering force in the DN development, but recent data have also pointed out an important role of the immune system and inflammation, as well as oxidative stress, lipotoxicity, and uremic toxins ( Moreno et al, 2018 ; Opazo-Ríos et al, 2020a ; Lavoz et al, 2020b ; Rayego-Mateos et al, 2020 ). At the molecular level, the importance of signaling pathways related to renal inflammation and fibrosis such as the loss of endothelial glucocorticoid receptor ( Srivastava et al, 2021b ), endothelial FGFR1 and SIRT3 signaling ( Li J. et al, 2017 ; Srivastava et al, 2018 ), TGFβ/SMAD, Notch, WNT/β-Catenin, and Sonic-Hedgehog pathways ( Marquez-Exposito et al, 2018 ; Zhao et al, 2018 ; Wang et al, 2022 ) have also demonstrated to play a relevant role in DN. Interestingly, despite good glycemic control, the inability to fully avoid chronic meta-inflammation (microinflammatory milieu caused by metabolic factors) could contribute to ESRD progression in diabetic patients.…”

Diagnostic significance of hsa_circ_0000146 and hsa_circ_0000072 biomarkers for Diabetic Kidney Disease in patients with type 2 diabetes mellitus

“…In addition, at high glucose concentrations, p38MAPK promotes cell proliferation, protein accumulation, and TGF-b, which ultimately results in DKD (22,23). In addition, the Wnt signaling cascade appears to play a crucial role in regulating the development of DKD in podocyte and mesangial cell damage and kidney AMPK signaling pathway 13 (1.6%) 1.9 × 10 -3 fibrosis (24). Angiotensin II (AngII), the principal peptide of RAS, promotes podocyte injury and reactive oxygen species production.…”

The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation

“…Multiple signaling pathways are involved in the pathological process of nephritis and renal fibrosis during DKD. For example, the Wnt signaling pathway is involved in the progression of DKD [ 28 ] and a variety of cellular behaviors, such as cell proliferation, migration, adhesion, and polarity [ 29 ]. Wnt/β-catenin regulates TGF-β1-mediated mesangial cell fibrosis and activates glycogen synthase kinase-3β (GSK-3β) signaling [ 30 ], thereby inducing mesangial cell fibrosis and apoptosis [ 26 ].…”