Diabetes Aggravates Post-ischaemic Renal Fibrosis through Persistent Activation of TGF-β1 and Shh Signalling

Abstract

Diabetes is a risk factor for acute kidney injury (AKI) and chronic kidney disease (CKD). Diabetic patients are easy to progress to CKD after AKI. Currently, activation of fibrotic signalling including transforming growth factor-β1 (TGF-β1) is recognized as a key mechanism in CKD. Here, we investigated the influence of diabetes on CKD progression after AKI by using a unilateral renal ischaemia–reperfusion injury (IRI) model in diabetic mice. IRI induced extensive tubular injury, fibrosis and lymphocyte recruitment at 3 weeks after IRI, irrespective of diabetes. However, diabetes showed sustained tubular injury and markedly increased fibrosis and lymphocyte recruitment compared with non-diabetes at 5 week after IRI. The mRNAs and proteins related to TGF-β1 and sonic hedgehog (Shh) signalling were significantly higher in diabetic versus non-diabetic IRI kidneys. During the in vitro study, the hyperglycaemia induced the activation of TGF-β1 and Shh signalling and also increased profibrogenic phenotype change. However, hyperglycaemic control with insulin did not improve the progression of renal fibrosis and the activation of TGF-β1 and Shh signalling. In conclusion, diabetes promotes CKD progression of AKI via activation of the TGF-β1 and Shh signalling pathways, but insulin treatment was not enough for preventing the progression of renal fibrosis.

Identification of Candidate Genes Involved in Renal Ischemia/Reperfusion Injury

“…These responses can evoke the anti-inflammatory and repair processes to initiate the recovery of the graft function (Sanchez-Nino et al , 2016 ; Pressly and Park, 2017 ). On the contrary, many factors released during the IRI, such as transforming growth factor-β, matrix metalloproteinases (MMPs), and altered extracellular matrix (ECM) components, can induce epithelial–mesenchymal transition, ECM remodeling, and interstitial fibrosis (Jain et al , 2000 ; Danobeitia et al , 2017 ; Kim et al , 2017 ; Liu et al , 2018 ), which hinder the recovery of complete function. Therefore, IRI is a complex and multistep pathological process that the mechanism has not been fully clarified yet.…”

Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice

“…Interstitial fibrosis, as determined by Sirius Red staining, tended to, but not significantly, increase in all diabetic mice compared to respective control mice (Supplemental Figure 4a), whereas no difference was observed among all diabetic mice. Renal expression levels of COL4A3 [31], TGF-β [32, 33], and CTGF [34], which are associated with renal fibrosis, were similar among all diabetic mice or all control mice, however, these levels were significantly increased in all diabetic mice compared to respective control mice (Supplemental Figure 4b, c, d).…”

Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner

“…Whereas there are a limited number of papers describing the effect of diet on outcomes of kidney disease, there is an appreciable literature available describing the effect of diabetes on the susceptibility and progression of kidney injury in rodents [ 30 , 31 , 32 , 33 ]. Ongoing (unpublished) studies in our lab suggest that mice fed the WD and AD have higher daily caloric intake (16 and 15 kcal/day, respectively) as compared to mice fed chow (12 kcal/day).…”