Vitamin D3 potentiates the renoprotective effects of vildagliptin in a rat model of fructose/salt-induced insulin resistance
Graphical abstract
Introduction
Kidney dysfunction is a major cause of morbidity and mortality whose prevalence is rising worldwide. In the wake of urbanization, surplus energy intake and sedentary life habits, the epidemics of insulin resistance (IR), might have played a role in increasing the prevalence of kidney injury. Hyperinsulinemia, which is inevitably associated to IR, also appears to badly affect kidney function by inducing glomerular hyperfiltration and increasing vascular permeability (De Cosmo et al., 2012).
The underlying mechanisms are still, however, not completely investigated, but include oxidative stress, inflammation, renal endothelial dysfunction, altered renal heamodynamics, activation of sympathetic nervous system and more recently, the interplay between renin angiotensin aldosterone system (RAAS) overactivation and vitamin D3 deficiency (Raimundo and Lopes, 2011; Ferder et al., 2013).
Infact, only small physiologic studies suggest real and direct negative renal impact of IR and compensatory hyperinsulinemia on eliciting kidney disease. Yet, when looking at larger database and prospective cohorts, it is less clear whether there is a distinct role of IR independently of coexisting diabetes (Whaley-Connell and Sowers, 2018). Therefore, there is a necessity to understand the metabolic relationships with chronic kidney disease (CKD) and to investigate whether treating IR and its associated metabolic derangements shall prevent development and progression of renal injury.
In this regard, the new incretin mimetics, dipeptidyl peptidase-4 inhibitors (DPP-4Is) have recently been shown to improve insulin sensitivity (Zheng et al., 2018) and exert beneficial pleiotropic effects, mainly through increasing the levels of glucagon-like peptide-1 (GLP-1). The latter acts primarily through binding to its pancreatic receptor (GLP-1R), triggering insulin secretion in β-cells, as well as inhibition of α-cell glucagon release (Rowlands et al., 2018). Prominently, GLP-1R is also expressed in the renal proximal tubules and glomerular capillaries (Pyke et al., 2014). Therefore, GLP-1 based therapies are reportedly beneficial to kidney function via increases in renal blood flow and urinary flow rate, prevention of rises in plasma creatinine, reduced tubular necrosis, increased glomerular filtration rate, as well as cytoprotective, anti-oxidative stress and anti-inflammatory actions (Jensen et al., 2015; Kodera and Shikata, 2016).
Mechanistically, Skov et al. (2014) have demonstrated that GLP-1 inhibits the post-receptor signaling pathway of angiotensin II, the matter that might be related to the improved insulin sensitivity through restoring the levels of adiponectin (Ran et al., 2006). Such effects may prevent the progression of IR-induced nephropathy.
Given the impact of IR and RAAS overactivation on the pandemic of vitamin D3 deficiency and the role of vitamin D3 supplementation in the downregulation of RAAS (Li, 2007; Vaidya and Forman, 2010), the question is raised whether vitamin D3 can be considered as an additional therapeutic agent against development and progression of IR-induced nephropathy.
The present study was therefore conducted to investigate the pleiotropic renoprotective effects of the DPP-4I, vildagliptin and vitamin D3 in a fructose/salt-induced IR rat model, shedding some light on the possible molecular mechanisms underlying their action. The study also aimed to evaluate the potential capacity of vitamin D3 to potentiate the renoprotective effects of vildagliptin.
Section snippets
Experimental animals
The current study was conducted using 50 adult male Wistar rats weighing 150–200 g. The animals were obtained from Faculty of Veterinary Medicine, Zagazig University (Egypt) and housed in plastic cages with wood shave bedding in the animal care unit at the Faculty of Pharmacy, Zagazig University, under a 12/12 h light/dark cycle with food and water ad libitum. The temperature and humidity of the animal house were kept constant (temperature 23 ± 2 °C, humidity 60 ± 10%) during the experiments.
Impact of fructose/salt consumption for 6 weeks on metabolic parameters and kidney function
As outlined in Table 1, a state of impaired fasting glucose, IR and compensatory hyperinsulinemia was verified 6 weeks after fructose/salt consumption, as evidenced by the significantly elevated FSG and FSI levels, as well as the HOMA-IR. It was of great interest that IR constellated with significant BW gain, atherogenic dyslipidemia (elevated serum TG, TC, LDL-C and AI and reduced HDL-C) and hyperuricemia, as compared to the control group (P < 0.05). In spite of the above-mentioned metabolic
Discussion
Data on the relationship between IR and non-diabetic CKD is sparse (Frankel and Kazempour-Ardebili, 2016). The present study has provided a more direct investigation of the precise role of IR in the incidence and progression of nephropathy. The study aimed to investigate the potential molecular mechanisms of vildagliptin and vitamin D3-induced nephroprotection in a fructose/salt-induced IR rat model, accentuating whether vitamin D3 can augment the renoprotective role of vildagliptin.
High
Conclusion
The current study has confirmed the pivotal role of either vildagliptin or vitamin D3 against development and progression of IR-induced nephropathy. It has indeed provided mounting evidence of the therapeutic potential of vitamin D3 to augment the nephroprotective effects of vildagliptin. Vildagliptin and vitamin D3 reversed hyperuricemia and seemed to exert a plethora of anti-oxidant, anti-inflammatory, anti-apoptotic and anti-fibrotic effects in kidney tissue. Our study has paid an attention
Compliance with ethical standards
We verify that this study has been approved by the Ethical Committee for Animal Handling at Zagazig University and has been carried out in accordance with the recommendations of Weatherall report.
Declaration of Competing Interest
None.
Acknowledgments
The authors received no financial support for the research. Prof. Dr. Dina Sabry, Professor of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, is acknowledged for her efforts in carrying out the molecular biology analysis.
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