Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats

Abstract

Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.

Investigation of the protective and therapeutic effects of β-aminoisobutyric acid (BAIBA) and Thymoquinone in the diabetic nephropathy

“…In previous studies, serum BUN and Cr amounts increased in DN induced by STZ (Omran, 2014;Giribabu et al, 2017;Khalilpour et al, 2019). Similarly, in the present study, serum BUN and Cr amounts increased in the STZ group compared with the control group.…”

“…Similarly, in the present study, serum BUN and Cr amounts increased in the STZ group compared with the control group. The increase of BUN and Cr amounts in the serum is an indicator of dysfunction and damage in the kidneys and is compatible with the histopathological findings obtained (Omran, 2014;Giribabu et al, 2017;Khalilpour et al, 2019). In the TQ and BAIBA groups, this data started to normalize and in the TQ + BAIBA group, this normalization was more successful than the other two groups.…”

“…In the current study, in the STZ group; while insulin level and body weight decreased compared with the control group, serum glucose amount and relative kidney weight increased. These findings overlap with the literature (Kanter, 2009;Ulu et al, 2012;Omran, 2014;Sameni et al, 2016;Rivoira et al, 2018;Khalilpour et al, 2019) While these data were almost identical with the control group in the TQ + BAIBA group, they were largely normalized in the TQ and BAIBA groups. Studies have shown that hyperglycemia causes an increase in kidney weight by increasing the amount of extracellular matrix in kidney tissue (Seyer-Hansen et al, 1980;Yajing et al, 2011;Sameni et al, 2016).…”

Accelerated degradation of collagen membranes in type 1 diabetic rats is associated with increased expression and production of several inflammatory molecules

“…It is one of the first molecules to arrive in a future inflammation site and is capable of inducing the production of other, classical, cytokines 45 . MIF levels are elevated in diabetics and this cytokine has been implicated in several diabetic complications, such as nephropathy, 46 retinopathy 47 etc. Since it is one of the earliest pro‐inflammatory cytokines, it is tempting to speculate that the reason we found it to be induced only at 2 weeks post‐surgery is that its levels decline later in the inflammatory process.…”

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…Wang et al described that the pharmacological blockade of MIF with ISO-1 in db/db mice induced a significant decrease in albuminuria, blood glucose levels, extracellular matrix deposition, EMT, and macrophage activation in damaged kidneys [136]. Moreover, the use of the MIF antagonist (p425) in STZ-induced diabetic rats, decreased the loss of renal function (protein excretion, UACR, and serum BUN and creatinine levels) [137].…”