Both hypertension and proteinuria are well-recognized major traditional risk factors for the progression
of CKD. In addition to hypertension and proteinuria there is evidence that ADMA could be directly involved in the progression of CKD. Indeed, in rats with a unilateral nephrectomy ADMA administration for 8 weeks in one group and its comparison with the other group that did not receive any ADMA, provided the following results: (i) Increased ADMA levels in serum are related to increased renal oxidative stress, since elevated renal levels of superoxide anion (O2−) were also found. (ii) ADMA administration had as a result the induction R788 of glomerular fibrosis (increase of synthesis of the intravascular substance), as well as vascular fibrosis, apparent by the increased collagen type I and II and fibronectin deposition. (iii) PD0325901 chemical structure In rats receiving ADMA, a decrease of the peritubular capillary network was noted. (iv) The mRNA expression of collagen type I and the renal concentration of TGF-β1 (transforming growth factor-β1) were
higher in rats receiving ADMA. (v) Elevated levels of TGF-β1 were correlated with the higher levels of angiotensin II as well as the increased expression of HIF-1a (hypoxia inducible factor-1a) and endothelin 1 (approximately thrice the normal levels). There is evidence suggesting that chronic renal hypoxia may have an important role in the progression of tubulointersttial fibrosis in CKD, and also the role of tubulointerstitial fibrosis is more important than glomerulosclerosis in terms of renal prognosis.[100, 101] The administration of a recombinant adenovirus vector, encoding DDAH-1 and resulting
in the increased expression of DDAH in rats with subtotal nephrectomy (5/6), the model that is currently considered as the most representative of kidney Atazanavir disease in human,[92, 102] has led to the decrease of ADMA concentrations and has slowed the progression of kidney damage, since the tubulointerstitial fibrosis was contained. This occurred to a larger extent compared with the rats with nephrectomy that received hydralazine aimed at the restoration of their blood pressure, suggesting that there is a mechanism for the progression of kidney damage totally independent to arterial hypertension. It is therefore suggested that the amelioration of ADMA levels has decreased the peritubularischaemia and lead to the decrease of TGF-β1 expression. Also in normal rats the chronic NOs inhabitation causes arterial hypertension and FSGS. Two studies have determined that there is a faster deterioration of renal function in CKD patients presenting with high ADMA serum concentrations, suggesting that it may act as an independent prognostic marker for the progression of renal disease.