Transient hypoxia‐inducible factor activation in rat renal ablation and reduced fibrosis with L‐mimosine

Abstract

There was a transient HIF-α activation in the remnant kidney of rats at the early stage following subtotal nephrectomy. L-mimosine administered in later stages re-activated HIF-α and reduced tubulointerstitial fibrosis.

miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation

“…Simultaneously, there was transient HIF-␣ activation in the remnant kidney of rats at the early stage following subtotal nephrectomy, which also peaked at weeks 4 and 6. L-Mim administered in later stages reactivated HIF-␣ and ameliorated the progression of CKD and renal interstitial fibrosis (56,57). In the present study, we found the abundance of a miRNA, miR-29c, which is known to suppress the expression of extracellular matrix genes (22), was decreased in the rat remnant kidney model as well as in human kidneys with TIF from IgA nephropathy patients.…”

“…The nuclear expression of HIF-␣ was upregulated in the early stage after 5 ⁄6 nephrectomy when renal function was stable and returned to the basal level later, accompanied by impaired renal function and interstitial fibrosis (56). During the same progression time course in the remnant kidney model, abundance of miR-29c was decreased at week 2 and gradually restored from week 4 to week 6, coinciding with the peak of HIF-␣ upregulation.…”

“…In our previous studies, we found that activation of HIF-␣ was dynamic during the disease progression in the remnant kidney model of CKD, which was activated transiently in the early stage and suppressed in the later stage; inhibition of PHDs using L-Mim activated HIF-␣ and attenuated the progression of CKD in the 5 ⁄6 nephrectomy model in a time-dependent manner (56). The renoprotective effect of the L-Mim treatment might be attributed to selective upregulation of renoprotective HIF target genes and/or downregulation of injurious genes at appropriate time points during disease progression.…”

“…In our previous studies, we found that chronic renal damages developed progressively in rats with 5 ⁄6 nephrectomy and that L-Mim intervention from week 5 to week 12 resulted in additional accumulation of HIF-1␣ and -2␣ at week 12 and improved renal function (56). To explore the role of microRNAs in this renoprotective phenomenon, we compared microRNA expression profiles in rats with 5 ⁄6 nephrectomy treated with L-Mim or vehicle (GEO accession no.…”

The HIF System Response to ESA Therapy in CKD‐Anemia

“…It was reported that HIF-α activation in CKD rats presents dynamic changes, as it is activated in early CKD stages and suppressed in the moderate and end-stage of CKD [95]. Thus, the administration of PHD inhibitors may improve renal function in more advanced stages of CKD, while in earlier stages, the PHD inhibitors may increase renal fibrosis due to upregulation of the HIF-1α subunit [22].…”