Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury–to–chronic kidney disease progression

Abstract

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure-lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure-lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

“…Other studies have found various hypomethylated genes associated with CKD (61,74,75). Methylation was shown to play a significant role in the progression of renal fibrosis (51)(52)(53)(54), supporting the role of demethylating agents in preventing or slowing the development of CKD. Currently, 2 demethylating agents are in clinical use, 5-azacytidine and decitabine, which are approved for the treatment of specific forms of myelodysplastic syndrome and acute myeloid leukemia (94).…”

“…Interestingly, DNMT1 expression, but not DNMT3a or DNMT3b expression, was increased in fibrotic mouse kidneys compared to control kidneys, which suggests a role of DNMT1 in the methylation of RASAL1 and the progression of kidney fibrosis. The importance of RASAL1 hypermethylation in the pathogenesis of kidney fibrosis has been confirmed in murine models of diabetic nephropathy induced by streptozotocin in CD1 mice, COL4A3-deficient Alport mice, unilateral ureteral obstruction, subtotal nephrectomy, folic acid nephropathy, and nephrotoxic serum nephritis (51)(52)(53)(54).…”

“…However, the drug has largely been superseded since angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were introduced (95). Hydralazine has long been known to possess demethylating activity (54). Hydralazine has been shown to display demethylating activity on a variety of tumor suppressor genes in patients with cervical cancer (98).…”

The prognostic value of abnormally expressed lncRNAs in colorectal cancer: A meta-analysis

“…Molecular Pathologic Epidemiology [56] is a relatively new, evolving field of epidemiology that is designed to clarify how various exposures affect initiation, transformation and progression of neoplasia[57]. It will continue to provide insights into carcinogenic process and help us to optimize prevention and treatment strategies[58].…”

Regulation of endogenous brakes to kidney fibrosis: turning the view upside down

“…There are some known drugs harboring epigenetic "side-effects" and that inadvertently have the potential to halt kidney disease. One such example is hydralazine, a compound known for its blood pressure lowering effects [8]. Thus, epigenetics holds the promise that this long known drug experiences a renaissance.…”