The Restoration of Vitamin D Levels Slows the Progression of Renal Ischemic Injury in Rats Previously Deficient in Vitamin D

Abstract

Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that nontraditional risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-β1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.

The association between obesity and vitamin D deficiency modifies the progression of kidney disease after ischemia/reperfusion injury

“…Corroborating our results, Decleves et al also observed increased renal and urinary expression of MCP-1 in mice fed a high-fat diet (35). In the present study, we also observed similar results concerning the renal expression of MCP-1, CD3+, and CD68+ cells in the VDD group, reinforcing the immunomodulatory effect of vitamin D (1,7,77). Of note, we found a higher renal expression of MCP-1, CD3+, and CD68+ cells in the HFDV group compared to all the other groups, demonstrating a synergistic effect of adipose tissue and vitamin D deficiency regarding the inflammatory process.…”

“…Furthermore, for knowledge and differentiation between the macrophage subtypes, we evaluated the proportion of CD206+ cells (M2 macrophages) in relation to the whole amount of macrophages stained with CD68 (M1+M2 macrophages, Figure 6C ). CD206 is also known as mannose receptor, which is an exclusive marker for M2 macrophages ( 1 , 34 ). Although without significance among the groups, we observed a downward tendency in the expression of CD206+ cells in the VDD, HFD, and HFDV groups in relation to the SD group ( Figures 6B,E ), reinforcing the role of vitamin D and adipose tissue on the modulation of renal inflammation.…”

“…Over the last few decades, there has been a growing interest in risk factors related to the progression of kidney disease. This fact is due to the high prevalence of chronic kidney disease (CKD) and its high costs, as well as the risk of progression to end-stage renal disease (1)(2)(3). In addition to advanced age, gender, and family history, there are other traditional and common risk factors related to the progression of kidney disease, including diabetes mellitus (DM), hypertension, obesity, and cardiovascular diseases (CVD) (3)(4)(5).…”

Treatment with β-blocker nebivolol ameliorates oxidative stress and endothelial dysfunction in tenofovir-induced nephrotoxicity in rats

“…Vascular endothelial damage triggers several pathological alterations displayed in the kidney disease progression ( 35 ). Treatment with nebivolol was also able to reverse kidney injury caused by long-term use of tenofovir, at least in part, due to its actions on pro-fibrotic molecules and inflammatory markers.…”

Evaluation of the Corticosteroid Receptors’ Level in the Kidneys of Rats After Systemic Ischemia-Reperfusion

“…It is controlled by central, intercellular, and intracellular regulatory mechanisms. During the period of an urgent generalized response to hypoxia, there is a simultaneous activation of various signaling systems of regulation and an increase in the urgent resistance of the body to oxygen deficiency [4]. The leading role in this process is played by the hypothalamus-pituitary-adrenal system and its main mediators-catecholamines and corticosteroids.…”