Chronic kidney disease (CKD) is characterized by loss of renal function. The pathological processes involved in the progression of this condition are already known, but the molecular mechanisms have not been completely explained. Recent reports have shown the intrinsic capacity of the kidney to undergo repair after acute injury through the reexpression of repairing proteins (Villanueva S, Cespedes C, Vio CP. Am J Physiol Regul Integr Comp Physiol 290: R861-R870, 2006). Stimulation with basic fibroblast growth factor (bFGF) could accelerate this process. However, it is not known whether bFGF can induce this phenomenon in kidney cells affected by CKD. Our aim was to study the evolution of renal damage in animals with CKD treated with bFGF and to relate the amount of repairing proteins with renal damage progression. Male Sprague-Dawley rats were subjected to 5/6 nephrectomy (NPX) and treated with bFGF (30 μg/kg, NPX+bFGF); a control NPX group was treated with saline (NPX+S). Animals were euthanized 35 days after bFGF administration. Functional effects were assessed based on serum creatinine levels; morphological damage was assessed by the presence of macrophages (ED-1), interstitial α-smooth muscle actin (α-SMA), and interstitial collagen through Sirius red staining. The angiogenic factors VEGF and Tie-2 and the epithelial/tubular factors Ncam, bFGF, Pax-2, bone morphogenic protein-7, Noggin, Lim-1, Wnt-4, and Smads were analyzed. Renal stem cells were evaluated by Oct-4. We observed a significant reduction in serum creatinine levels, ED-1, α-SMA, and Sirius red as well as an important induction of Oct-4, angiogenic factors, and repairing proteins in NPX+bFGF animals compared with NPX+S animals. These results open new perspectives toward reducing damage progression in CKD.

In angiotensin II (Ang II)-dependent hypertensive rats there is an increased expression of proximal tubule angiotensinogen (AGT), collecting duct renin and angiotensin converting enzyme (ACE), which contributes to intratubular Ang II formation. Ang II acts on Ang II type 1 receptors promoting sodium retention and vasoconstriction. However concurrently, the ACE2-Ang-(1-7) axis and the expression of kallikrein and medullary prostaglandins counteract the effects of Ang II, promoting natriuresis and vasodilation. Human studies demonstrate that dietary potassium (K+) intake lowers blood pressure. In this report we evaluate the expression of AGT, ACE, medullary prorenin/renin, ACE2, kallikrein and cyclooxygenase-2 (COX-2) in Ang II-infused rats fed with high K+ diet (2%) for 14 days. Dietary K+ enhances diuresis in non-infused and in Ang II-infused rats. The rise in systolic blood pressure in Ang II-infused rats was attenuated by dietary K+. Ang II-infused rats showed increased renal protein levels of AGT, ACE and medullary prorenin and renin. This effect was attenuated in the Ang II + K+ group. Ang II infusion decreased ACE2 compared to the control group; however, K+ diet prevented this effect in the renal medulla. Furthermore, medullary COX-2 was dramatically induced by K+ diet in non-infused and in Ang II infused rats. Dietary K+ greatly increased kallikrein immunostaining in normotensive rats and in Ang II-hypertensive rats. These results indicate that a high K+ diet attenuates Ang II-dependent hypertension by preventing the induction of ACE, AGT and collecting duct renin and by enhancing medullary COX-2 and ACE2 protein expression in the kidney.

The importance of dietary potassium in health and disease has been underestimated compared with that placed on dietary sodium. Larger effort has been made on reduction of sodium intake and less on the adequate dietary potassium intake, although natural food contains much more potassium than sodium. The benefits of a potassium-rich diet are known, however, the mechanism by which it exerts its preventive action, remains to be elucidated. With the hypothesis that dietary potassium reduces renal vasoconstrictor components of the renin-angiotensin system in the long-term, we studied the effect of high potassium diet on angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2.

The mechanism of hypertension-induced renal fibrosis is not well understood, although it is established that high levels of angiotensin II contribute to the effect. Since β-catenin signal transduction participates in fibrotic processes, we evaluated the contribution of β-catenin-dependent signaling pathway in hypertension-induced renal fibrosis. Two-kidney one-clip (2K1C) hypertensive rats were treated with lisinopril (10 mg/kg/day for four weeks) or with pyrvinium pamoate (Wnt signaling inhibitor, single dose of 60 ug/kg, every 3 days for 2 weeks). The treatment with lisinopril reduced the systolic blood pressure from 220 ± 4 in 2K1C rats to 112 ± 5 mmHg (P < 0.05), whereas the reduction in blood pressure with pyrvinium pamoate was not significant (212 ± 6 in 2K1C rats to 170 ± 3 mmHg, P > 0.05). The levels of collagen types I and III, osteopontin, and fibronectin decreased in the unclipped kidney in both treatments compared with 2K1C rats. The expressions of β-catenin, p-Ser9-GSK-3beta, and the β-catenin target genes cyclin D1, c-myc, and bcl-2 significantly decreased in unclipped kidney in both treatments (P < 0.05). In this study we provided evidence that β-catenin-dependent signaling pathway participates in the renal fibrosis induced in 2K1C rats.

Chronic hypoxia has been postulated as one of the mechanisms involved in salt-sensitive hypertension and chronic kidney disease (CKD). Kidneys have a critical role in the regulation of arterial blood pressure through vasoactive systems, such as the renin-angiotensin and the kallikrein-kinin systems, with the angiotensin-converting enzyme (ACE) and kallikrein being two of the main enzymes that produce angiotensin II and bradykinin, respectively. Neutral endopeptidase 24.11 or neprilysin is another enzyme that among its functions degrade vasoactive peptides including angiotensin II and bradykinin, and generate angiotensin 1-7. On the other hand, the kidneys are vulnerable to hypoxic injury due to the active electrolyte transportation that requires a high oxygen consumption; however, the oxygen supply is limited in the medullary regions for anatomical reasons. With the hypothesis that the chronic reduction of oxygen under normobaric conditions would impact renal vasoactive enzyme components and, therefore; alter the normal balance of the vasoactive systems, we exposed male Sprague-Dawley rats to normobaric hypoxia (10% O2) for 2 weeks. We then processed renal tissue to identify the expression and distribution of kallikrein, ACE and neutral endopeptidase 24.11 as well as markers of kidney damage. We found that chronic hypoxia produced focal damage in the kidney, mainly in the cortico-medullary region, and increased the expression of osteopontin. Moreover, we observed an increase of ACE protein in the brush border of proximal tubules at the outer medullary region, with increased mRNA levels. Kallikrein abundance did not change significantly with hypoxia, but a tendency toward reduction was observed at protein and mRNA levels. Neutral endopeptidase 24.11 was localized in proximal tubules, and was abundantly expressed under normoxic conditions, which markedly decreased both at protein and mRNA levels with chronic hypoxia. Taken together, our results suggest that chronic hypoxia produces focal kidney damage along with an imbalance of key components of the renal vasoactive system, which could be the initial steps for a long-term contribution to salt-sensitive hypertension and CKD.