Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats

Abstract

Abstract. The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases.

Snail, a transcriptional regulator, represses nephrin expression in glomerular epithelial cells of nephrotic rats

“…Proteinuric diseases, such as minimal change nephropathy, focal segmental glomerulosclerosis, lupus nephritis, and diabetic nephropathy in human and experimental nephropathy in animals show a perturbation of slit diaphragm and a decrease in the expression level of nephrin. [8][9][10][11][12][13][14][15][16][17][18] Although null or decreased expression of nephrin is closely related to podocyte dysfunction and proteinuria, little is known about the transcriptional regulation of nephrin.…”

“…18 Nephrin expression is also under the control of some other signaling pathways in addition to it's regulation by retinoic acids. Wanger et al 19 found Wilms' tumor suppressor (WT-1) transcriptionally activates nephrin.…”

Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

“…This antiproteinuric effect occurred as early as week 2 after treatment. Treatment with atRA has also been reported to decrease proteinuria in other models of kidney disease [23][24][25] . It is well known that defects in the glomerular filtration barrier lead to proteinuria [35] , and that podocytes play a pivotal role in glomerular barrier function [36,37] .…”

“…It is well known that defects in the glomerular filtration barrier lead to proteinuria [35] , and that podocytes play a pivotal role in glomerular barrier function [36,37] . The upregulation of nephrin and podocin in podocytes by atRA, in vivo and in vitro, was proposed as a possible mechanism for its antiproteinuric effect [23,24] . Because proteinuria is also a risk factor for the progression of renal diseases [38] , a decrease in proteinuria at least partly mediates the renoprotective effects of atRA.…”

“…They act via the retinoic acid receptor (RAR) and retinoid X receptor (RXR), which serve as transcription factors to regulate target gene expression. Retinoids have been reported to be renoprotective in some models of renal fibrosis [20][21][22][23][24][25][26][27][28] . We have previously shown that exogenous atRA decreases cardiac fibrosis in spontaneously hypertensive rats (SHR) [29] and inhibits the increases in PAI-1 and the ECM protein fibronectin, which are induced by the key fibrogenic cytokines transAmelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin www.chinaphar.com Liu X et al Acta Pharmacologica Sinica npg forming growth factor-β1 (TGF-β1) and angiotensin II (Ang II) in cultured rat mesangial cells [30] .…”