Renal inflammation is modulated by potassium in chronic kidney disease: possible role of Smad7

Abstract

High-potassium diets have been shown to be beneficial in cardiovascular disease partly because of a blood pressure-lowering effect. The effect of potassium on inflammation has not been studied. We investigated the influence of potassium supplementation on the degree of renal inflammation and the intracellular signaling mechanisms that could mediate inflammation in chronic kidney disease (CKD). CKD was created in male SpragueDawley rats by subtotal nephrectomy. Two groups of CKD rats were pair fed with diets containing 2.1% potassium (potassium-supplemented diet) or 0.4% potassium (basal diet). Body weight, blood pressure, and blood and urine electrolytes were measured biweekly. The animals were euthanized at week 8, and the remnant kidneys were analyzed by histology, immunohistochemistry, Western blotting, and real-time quantitative PCR. In the CKD pair-fed groups, blood potassium concentration did not differ significantly, but blood pressure was lower in the potassium-supplemented group. Compared with the basal diet, potassium supplementation decreased renal tubulointerstitial injury and suppressed renal inflammation as evidenced by decreased macrophage infiltration, lower expression of inflammatory cytokines, and decreased NF-B activation. These renoprotective effects were associated with downregulation of renal transforming growth facto-␤, upregulation of renal Smad7, and lower blood pressure. Our results show that potassium supplementation can reduce renal inflammation and hence, could modulate the progression of kidney injury in CKD.NF-B; potassium; Smad7; TGF-␤ THE MEDIATORS OF PROGRESSIVE chronic kidney disease (CKD) remain largely unsolved, especially the mechanisms leading to progressive fibrosis of the kidney. The presence of fibrosis in the kidney is generally preceded by glomerular and tubulointerstitial infiltration by inflammatory cells. It is likely that the infiltrating inflammatory cells activate NF-B, leading to the production and release of proinflammatory cytokines and adhesion molecules (e.g., IL-1␤, ICAM-1) as well as profibrotic cytokines [e.g., transforming growth factor (TGF)-␤]. The consequence is renal inflammation and progressive fibrosis of the kidney, leading to loss of function. Treatment strategies have included medications and dietary modifications such as limitation of protein and sodium intake to reduce the accumulation of potential uremic toxins and blood pressure. The potential influence of potassium intake on progressive kidney disease remains largely unknown.There are indications that potassium supplementation may be beneficial in cardiovascular diseases, especially for problems arising as a complication of hypertension (7,17,20,27,38). There are also indications that potassium supplementation might reduce local vascular inflammatory reactions. Ishimitsu et al. (16) reported that potassium supplementation suppressed macrophage activity in stroke-prone spontaneously hypertensive rats (SHPsp). In their study, the rats were fed a normal or high-potassium diet, and excised aort...

Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia

“…Similar ultrastructural changes in the kidney epithelia leading to polyuria and electrolyte wasting as described here for Mim -/-mice 1249 MIM/MTSS1 maintains kidney epithelia integrity were previously detected in mice lacking tight junction component claudin-16, as well as in humans suffering from cystic kidney disease nephronophthisis and kaliopenic nephropathy (Hou et al, 2007;Krishnan et al, 2008;Simon et al, 1999;Wang, W. et al, 2007b). This suggests that defects in cell-cell contacts compromising epithelial integrity can reduce osmotic gradient for effective water reabsorption or might result in backflow of water through the junctional space, and thus lead to polyuria.…”

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

“…A similar result has been reported using models of unilateral ureteral obstruction where the genetic ablation of B 2 R or its pharmacological blockade increased interstitial fibrosis by reducting ECM degradation (44). However, the existence of a link among the kinin system, a high-potassium diet, and changes in TGF-␤ has not been explored to date (54). This evidence and the fact that acquired salt sensitivity can follow overload proteinuria (2) prompted us to investigate the effects of albumin overload on the kinin system and TGF-␤ in the kidney using both animal and in vitro models.…”

Association of Hypo- and Hyperkalemia with Disease Progression and Mortality in Males with Chronic Kidney Disease: The Role of Race

“…To our knowledge, prior to our study low potassium has not been described as a risk factor for progressive CKD. The proposed mechanism underlying the deleterious effects of lower potassium on kidney function includes direct tubulointerstitial injury via modulation of renal inflammation [6], local activation of the renin-angiotensin system [47], increased expression of angiotensin II receptors [48] or indirect effects through worsening hypertension. Another possible mechanism of action entails generation of excess ammonia in the proximal convoluted tubule in response to hypokalemia [49].…”

“…Abnormal potassium values have been associated with mortality in dialysis patients [2,3], and more recently also in patients with various degrees of non-dialysis-dependent CKD (NDD-CKD) [4]. Besides the short-term arrhythmogenic effects of hypo- and hyperkalemia, potassium may also have an indirect impact on clinical outcomes through inflammation, oxidative stress, renal interstitial fibrosis, vascular biology and blood pressure [5,6,7,8,9,10]. The role of potassium is even more complicated in patients with NDD-CKD, in whom abnormal potassium levels may unduly hinder the administration of medications with benefits on clinical outcomes such as angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs).…”