Effects of Progranulin Deficiency on Inflammation and Fibrosis in the Kidneys and Liver of Diabetic Mice Fed a High-Fat Diet.

Abstract

Background: Progranulin (PGRN) is an important regulator of inflammation, insulin resistance, and autophagy. However, the effects of PGRN deficiency on these processes in the kidneys and liver in diabetes remain unclear. In addition, the differential effects of PGRN deficiency and sodium-glucose co-transporter-2 (SGLT2) inhibitors on these organs are unknown.

Methods: Three diabetic mouse models were used: high-fat diet and nicotinamide/streptozotocin-induced diabetic wild-type (WT) and PGRN-knockout (KO) mice (WT-diabetes mellitus [DM] and KO-DM, respectively) and WT-DM mice treated with an SGLT2 inhibitor (tofogliflozin; WT-DM/Tofo).

Results: Despite similar glycemic control in WT-DM/Tofo and KO-DM mice, expression of inflammation- and fibrosis-related genes in the kidneys was highest in WT-DM mice, lower in KO-DM mice, and lowest in WT-DM/Tofo mice. WT-DM/Tofo mice also showed increased anti-microtubule-associated protein 1A/1B-light chain 3B and decreased p62 protein levels compared with KO-DM mice. In contrast, hepatic mRNA levels related to inflammation and fibrosis were improved in both WT-DM/Tofo and KO-DM mice. Moreover, hepatic protein levels of peroxisome proliferator-activated receptor γ (PPARγ) were elevated in both groups compared with WT-DM mice, while those of PPARα were increased in WT-DM/Tofo mice compared with both WT-DM and KO-DM mice.

Conclusion: Kidney inflammation and fibrosis were ameliorated in WT-DM/Tofo mice, but these improvements were limited by autophagy insufficiency in KO-DM mice. Additionally, both WT-DM/Tofo and KO-DM mice demonstrated improved liver inflammation and fibrosis; in the former, this was associated with enhanced fatty acid oxidation via PPARα activation, while in the latter, it appeared to result from improved insulin sensitivity and anti-inflammatory effects through PPARγ activation.