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

Abstract

Acute kidney injury (AKI) alters renal hemodynamics, leading to tubular injury, activating pathways of inflammation, proliferation, and cell death. The initial damage caused to renal tissue after an ischemia/reperfusion (I/R) injury exerts an important role in the pathogenesis of the course of AKI, as well as in the predisposition to chronic kidney disease. Vitamin D deficiency has been considered a risk factor for kidney disease and it is associated with tubulointerstitial damage, contributing to the progression of kidney disease. Obesity is directly related to diabetes mellitus and hypertension, the main metabolic disorders responsible for the progression of kidney disease. Furthermore, the expansion of adipose tissue is described as an important factor for increased secretion of pro-inflammatory cytokines and their respective influence on the progression of kidney disease. We aimed to investigate the influence of vitamin D deficiency and obesity on the progression of renal disease in a murine model of renal I/R. Male Wistar rats underwent renal I/R surgery on day 45 and followed until day 90 of the protocol. We allocated the animals to four groups according to each diet received: standard (SD), vitamin D-depleted (VDD), high fat (HFD), or high fat vitamin D-depleted (HFDV). At the end of 90 days, we observed almost undetectable levels of vitamin D in the VDD and HFDV groups. In addition, HFD and HFDV groups presented alterations in the anthropometric and metabolic profile. The combination of vitamin D deficiency and obesity contributed to alterations of functional and hemodynamic parameters observed in the HFDV group. Moreover, this combination favored the exacerbation of the inflammatory process and the renal expression of extracellular matrix proteins and phenotypic alteration markers, resulting in an enlargement of the tubulointerstitial compartment. All these changes were associated with an increased renal expression of transforming growth factor β and reduced expression of the vitamin D receptor. Our results show that the synergistic effect of obesity and vitamin D deficiency exacerbated the hemodynamic and morphological changes present in the evolution of renal disease induced by I/R.

Vitamin D deficiency contributes to the diabetic kidney disease progression via increased ZEB1/ZEB2 expressions

“…Our data demonstrated an increase in EMT in the VitD-de cient diabetic rats. Similar to our ndings, previous studies have also demonstrated that VitD de ciency is related to increased expression of vimentin and α-SMA in tubular and tubulointerstitial cells, respectively, of the rats submitted to a high-fat diet [42] and in rats euthanized 60 days after I/R injury [36]. Increased expression of α-SMA and vimentin may contribute to the accumulation of ECM and consequent tubulointerstitial brosis considered the end common pathway to all progressive kidney diseases and which can culminate in ESRD [40].…”

Vitamin D deficiency contributes to the diabetic kidney disease progression via increase ZEB1/ZEB2 expressions

“…Our data demonstrated an increase in EMT in the VitD-deficient diabetic rats. Similar to our findings, previous studies have also demonstrated that VitD deficiency is related to increase expression of vimentin and α-SMA in tubular and tubulointerstitial cells, respectively, of the rats submitted to a high-fat diet [ 43 ] and in rats euthanized sixty days after I/R renal injury [ 38 ]. An increase in the desmin, vimentin and α-SMA expressions may contribute to the accumulation of ECM and consequent glomerulosclerosis and tubulointerstitial fibrosis considered the end common pathway to all progressive kidney diseases and which can culminate in ESRD [ 42 , 44 ].…”

Influência da deficiência de vitamina D na evolução da nefropatia diabética

“…Portanto, o rim além de principal local de ativação da VitD é também um importante sítio de ação desse hormônio (Manucha, Juncos, 2017;Hu et al, 2019), sendo sua deficiência amplamente relatada na DRC (Holick, 2007;Li, 2010). Nesse sentido, estudos experimentais demonstraram que a deficiência de VitD está relacionada a piora das lesões renais na DRC (Gonçalves et al, 2014;Felício et al, 2016;Bragança et al, 2018;Almeida et al, 2019;Bernardo et al, 2022) e tem sido considerada como um dos potenciais fatores de risco ao desenvolvimento e progressão da ND em pacientes (Felício et al, 2016;Nakashima et al, 2016;Xiao et al, 2016;Felício et al, 2017;Fan et al, 2018). Contudo, os mecanismos relacionados com o efeito da sua deficiência na progressão da lesão renal não foram ainda completamente elucidados.…”

“…Portanto, a TEM é caracterizada pela repressão de genes relacionados ao fenótipo epitelial, como da E-caderina, de proteínas de junções apertadas e citoqueratinas, e indução da expressão de genes relacionados ao fenótipo mesenquimal, como da Ncaderina, alfa-actina do músculo liso (α-SMA), desmina e vimentina (Essawy et al, 1997;Caja, Tan, 2019). Estudos demonstraram que a deficiência de VitD contribuiu para o aumento da deposição de proteínas de MEC e alteração fenotípica das células túbulointersticiais sugerindo aumento da TEM nos rins de ratos em diferentes modelos de DRC (Gonçalves et al, 2014;Bragança et al, 2018;Bernardo et al, 2022). Contudo, pouco se sabe sobre os mecanismos moleculares pelos quais a deficiência de VitD leva ao desenvolvimento e progressão desse processo durante a fibrose renal.…”

“…Foi constatado ainda que o aumento da inflamação está relacionado com aumento do estresse oxidativo e da TEM em cultura de células submetidas a altas concentrações de glicose em biópsias de tecido renal de pacientes com DM2 (Huang et al, 2022). Estudos recentes demonstraram que a inflamação estava associada com aumento da expressão de marcadores de TEM e fibrose renal em ratos nefrectomizados (Gonçalves et al, 2020) e ratos obesos (Bernardo et al, 2022) deficientes em VitD. Apesar disso, os mecanismos envolvidos na relação entre desestabilização endotelial/TEM/inflamação na deficiência de VitD durante a progressão da ND, principalmente, em modelos experimentais de diabetes tipo 1 ainda não foram totalmente esclarecidos.…”