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

2007 ◽  
Vol 293 (4) ◽  
pp. F1123-F1130 ◽  
Author(s):  
Wansheng Wang ◽  
Liliana Soltero ◽  
Ping Zhang ◽  
Xiao R. Huang ◽  
Hui Y. Lan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intracellular Signaling ◽  
Basal Diet ◽  
Sprague Dawley ◽  
Blood Pressure Lowering Effect ◽  
High Potassium ◽  
Renal Inflammation ◽  
Potassium Supplementation

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 Sprague-Dawley 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-κB activation. These renoprotective effects were associated with downregulation of renal transforming growth facto-β, 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.

MO443EFFECTS OF SHORT-TERM POTASSIUM CHLORIDE SUPPLEMENTATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Martin Gritter ◽  
Rosa Wouda ◽  
Stanley Ming Hol Yeung ◽  
Liffert Vogt ◽  
Martin De Borst ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ammonium Excretion ◽  
Short Term ◽  
Open Label ◽  
High Potassium ◽  
Renin Angiotensin ◽  
Lower Baseline

Abstract Background and Aims A high potassium (K+) diet is part of a healthy lifestyle and reduces blood pressure. Indeed, salt substitution (replacing NaCl by KCl) reduces the incidence of hypertension. Furthermore, emerging data show that high urinary K+ excretion in patients with chronic kidney disease (CKD) is associated with better kidney outcomes. This suggests that higher dietary K+ intake is also beneficial for patients with CKD, but a potential concern is hyperkalemia. Thus, there is a need for data on the effects of KCl supplementation in patients with CKD. Methods The effect of KCl supplementation (40 mEq/day) was studied by analyzing the 2-week open-label run-in phase of an ongoing randomized clinical trial studying the renoprotective effects of 2-year K+ supplementation in patients with progressive CKD and hypertension. The aims were to (1) analyze the effects of KCl supplementation on whole-blood K+ (WBK+) and acid-base balance, (2) identify factors associated with a rise in WBK+, and (3) identify risk factors for hyperkalemia (WBK+ > 5.5 mEq/L) . Results In 200 patients (68 ± 11 years, 74% males, eGFR 32 ± 9 mL/min/1.73 m2, 84% on renin-angiotensin inhibitors, 39% with diabetes mellitus), KCl supplementation increased urinary K+ excretion from 73 ± 24 to 106 ± 29 mEq/day, urinary chloride excretion from 144 ± 63 to 174 ± 60 mEq/day, WBK+ from 4.3 ± 0.5 to 4.7 ± 0.6 mEq/L, and plasma aldosterone from 294 to 366 ng/L (P < 0.01 for all). Plasma chloride increased from 104 ± 4 to 106 ± 4 mEq/L, while plasma bicarbonate decreased from 24.4 ± 3.4 to 23.6 ± 3.5 mEq/L and venous pH from 7.36 ± 0.03 to 7.34 ± 0.04 (P < 0.001 for all); urinary ammonium excretion did not increase (stable at 17.2 mEq/day). KCl supplementation had no significant effect on plasma renin (33 to 39 pg/mL), urinary sodium excretion (156 ± 63 to 155 ± 65 mEq/day), systolic blood pressure (134 ± 16 to 133 ± 17 mm Hg), eGFR (32 ± 9 to 31 ± 8 mL/min/1.73 m2) or albuminuria (stable at 0.2 g/day). Multivariable linear regression identified that age, female sex, and renin-angiotensin inhibitor use were associated with an increase in WBK+, while diuretic use, baseline WBK+, and baseline bicarbonate were inversely associated with a change in WBK+ after KCl supplementation (Table 1). The majority of patients (n = 181, 91%) remained normokalemic (WBK+ 4.6 ± 0.4 mEq/L). The 19 patients who did develop hyperkalemia (WBK+ 5.9 ± 0.4 mEq/L) were older (75 ± 8 vs. 67 ± 11 years), had lower eGFR (24 ± 8 vs. 32 ± 8 mL/min/1.73 m2), lower baseline bicarbonate (22.3 ± 3.6 vs. 24.6 ± 3.3 mEq/L), higher baseline WBK+ (4.8 ± 0.4 vs. 4.2 ± 0.4 mEq/L), and lower baseline urinary K+ excretion (64 ± 16 vs. 73 ± 25 mEq/day, P < 0.05 for all). Conclusions The majority of patients with advanced CKD remains normokalemic upon KCl supplementation, despite low eGFR, diabetes mellitus, or the use of renin-angiotensin inhibitors. This short-term study illustrates the feasibility of investigating the renoprotective potential of increased K+ intake or KCl-enriched salt in patients with CKD and provides the characteristics of patients in whom this is safe. Our study also shows that KCl supplementation causes a tendency towards metabolic acidosis, possibly by preventing an increase in ammoniagenesis. Longer-term studies are required to study the anti-hypertensive and renoprotective potential of K+ supplementation.

scholarly journals Intermittent hypoxia exacerbates increased blood pressure in rats with chronic kidney disease

2018 ◽  
Vol 315 (4) ◽  
pp. F927-F941 ◽  
Author(s):  
Jennifer L. Riggs ◽  
Carolyn E. Pace ◽  
Heather H. Ward ◽  
Laura V. Gonzalez Bosc ◽  
Lynnette Rios ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intermittent Hypoxia ◽  
Interstitial Fibrosis ◽  
Control Diet ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Plasma Creatinine ◽  
Sprague Dawley

Kidney injury and sleep apnea (SA) are independent risk factors for hypertension. Exposing rats to intermittent hypoxia (IH) to simulate SA increases blood pressure whereas adenine feeding causes persistent kidney damage to model chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would exacerbate the development of hypertension and renal failure. Male Sprague-Dawley rats were fed a 0.2% adenine diet or control diet (Control) until blood urea nitrogen was >120 mg/dl in adenine-fed rats (14 ± 4 days, mean ± SE). After 2 wk of recovery on normal chow, rats were exposed to IH (20 exposures/h of 5% O2-5% CO2 7 h/day) or control conditions (Air) for 6 wk. Mean arterial pressure (MAP) was monitored with telemeters, and plasma and urine samples were collected weekly to calculate creatinine clearance as an index of glomerular filtration rate (GFR). Prior to IH, adenine-fed rats had higher blood pressure than rats on control diet. IH treatment increased MAP in both groups, and after 6 wk, MAP levels in the CKD/IH rats were greater than those in the CKD/Air and Control/IH rats. MAP levels in the Control/Air rats were lower than those in the other three groups. Kidney histology revealed crystalline deposits, tubule dilation, and interstitial fibrosis in both CKD groups. IH caused no additional kidney damage. Plasma creatinine was similarly increased in both CKD groups throughout whereas IH alone increased plasma creatinine. IH increases blood pressure further in CKD rats without augmenting declines in GFR but appears to impair GFR in healthy rats. We speculate that treating SA might decrease hypertension development in CKD patients and protect renal function in SA patients.

scholarly journals Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1600-1612
Author(s):  
Dominique M. Bovée ◽  
Liwei Ren ◽  
Estrellita Uijl ◽  
Marian C. Clahsen-van Groningen ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Mean Arterial Pressure ◽  
Kidney Disease ◽  
Arterial Pressure ◽  
Small Interfering Rna ◽  
Ang Ii ◽  
Blood Pressure Lowering Effect ◽  
Independent Manner ◽  
Interfering Rna

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.

P0685RENAL SUBCAPSULAR ADIPOSE-DERIVED MESENCHYMAL STEM CELLS (ASC) ADMINISTRATION, ASSOCIATED TO LOSARTAN TREATMENT, PREVENTED THE PROGRESSION OF RENAL DAMAGE IN AN EXPERIMENTAL MODEL OF CHRONIC KIDNEY DISEASE (CKD)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Marina P Claro ◽  
Krislley R Pereira ◽  
Everidiene K V B Silva ◽  
Flavio Teles ◽  
Paulyana F Barbosa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Kidney Disease ◽  
Wistar Rats ◽  
Renal Inflammation ◽  
Male Wistar Rats ◽  
Losartan Treatment

Abstract INTRODUCTION / AIMS Chronic kidney disease (CKD) is considered a public health problem with epidemic proportions worldwide. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to the establishment of a chronic self-sustained renal inflammation, are the main factors which contribute to the progression of CKD, leading to tissue fibrosis and loss of function. Consequently, RAAS inhibitors, such as the AT-1 receptor antagonist, Losartan, are among the most currently employed therapeutic strategies to slow down CKD progression, although the renoprotection afforded by these drugs is not complete. The association of anti-inflammatory and immunosuppressive drugs to RAAS inhibition is limited to the treatment of specific nephropathies, and its safety is still not entirely known. In this context, experimental application of mesenchymal stem cells (mSC) as a treatment to control renal inflammation and fibrosis have been showing promising results in studies with animal models of CKD. The aim of the present study was to analyze the renoprotective effects of subcapsular application of adipose-tissue derived mSC (ASC), associated to Losartan treatment, in rats submitted to 5/6 nephrectomy, after the establishment of CKD. METHODS ASC were isolated from gonadal adipose tissue from male Wistar rats, cultured until P4 and characterized by flow cytometry and in vitro differentiation. Male Wistar rats underwent 5/6 nephrectomy and were followed for 15 days to confirm the establishment of the nephropathy (CKD 15d). After this period, animals underwent a new surgery in which they received a subcapsular injection of 10 μL of sterile PBS (vehicle), or 2x106 ASC diluted in 10 μL of sterile PBS. Part of these animals were than treated orally with 50 mg/kg/day of Losartan (LOS) for further 15 days (groups CKD + LOS 30d and CKD + LOS + ASC 30d). A group of animals that received only subcapsular vehicle were kept untreated for the same period (CKD 30d). Sham-operated rats, euthanized at days 15 (Sham 15d) and 30 (Sham 30d), were used as controls. Survival rate, body weight (BW), systolic blood pressure (BP), 24h urinary protein (24h UPE) and albumin (24h UAE) excretion, serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations, percentage (GS%) and index (GSI) of glomerulosclerosis, percentage of tubulointerstitial fibrosis (INT%) and renal infiltration by macrophages (CD68) were assessed 15 and 30 days after 5/6 nephrectomy. The obtained results are presented as Mean ± SE. Differences among groups were analyzed by one-way ANOVA. RESULTS The renal subcapsular application of ASC after the establishment of severe CKD improved the renoprotection obtained with the classic treatment with LOS. The association of LOS + ASC significantly improved animal’s survival, reduced blood pressure, proteinuria and albuminuria, prevented the development of glomerular structural damage and interstitial fibrosis, and inhibited renal inflammation by normalizing renal macrophage infiltration in the CKD + LOS + ASC group. CONCLUSIONS Our preliminary results demonstrate that the application of ASC, associated to the oral administration of LOS exerted additional renoprotection in the 5/6 renal ablation model, compared to LOS monotherapy. These findings suggest that ASC therapy could be employed as a therapeutic additive together with the traditional RAAS blockade, to detain the progression of CKD.

Abstract MP32: Effectiveness Of Investigational RNAi Therapeutics Targeting Liver Angiotensinogen In Experimental Chronic Kidney Disease

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Dominique M Bovee ◽  
Liwei Ren ◽  
Don Foster ◽  
A.H. J Danser
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Combination Treatment ◽  
Heart Weight ◽  
Similar Degree ◽  
Sprague Dawley ◽  
Vehicle Treatment ◽  
Rnai Therapeutics ◽  
Pressure Independent

Background: RNAi therapeutics targeting angiotensinogen (AGT) lower blood pressure in animal models of essential hypertension, but whether this treatment is beneficial in hypertensive chronic kidney disease (CKD) is yet unknown. Our aim was to assess the effectiveness of a small interfering RNA (siRNA) targeting hepatic AGT in a rat model of hypertensive CKD. Methods: Sprague Dawley rats (n=7-12 per group) were subjected to 5/6th nephrectomy, allowed to recover for four weeks, and subsequently subjected to one of five treatments: (1) vehicle, (2) AGT siRNA (10-30 mg/kg, s.c. every 2 weeks), (3) AGT siRNA + losartan (30 mg/kg/d), (4) losartan (30 mg/kg/d), or (5) losartan + captopril (30 and 6 mg/kg/d). Mean arterial pressure (MAP) was measured by radiotelemetry for 4 weeks, glomerular filtration rate (GFR) was measured by transcutaneous FITC-sinistrin clearance. Results: AGT siRNA and AGT siRNA + losartan reduced plasma AGT by 96.5 ± 1.4% and 97.0 ± 2.3%, respectively. Over the course of 4 weeks, proteinuria increased with vehicle and this increase was abrogated by all treatments (Δ proteinuria at 4 weeks versus baseline: +0.17 [0.12, 0.23], +0.02 [-0.04, 0.05], -0.01 [-0.07, 0.06], -0.05 [-0.12, 0.00], -0.01 [-0.06, 0.11] for vehicle, AGT siRNA, AGT siRNA + losartan, losartan, losartan + captopril, P < 0.05 for all groups compared with vehicle). Similarly, heart weight was equally reduced by all treatments except vehicle. No intervention affected GFR. Over the course of 4 weeks, MAP increased (from a baseline of 154 ± 18 mmHg) during vehicle treatment and this rise was prevented by AGT siRNA (+13 ± 15 mmHg vs. -2 ± 14 mmHg, P > 0.05 for difference between groups). Combination treatment with AGT siRNA + losartan, losartan + captopril, and losartan alone caused a similar and marked reduction in MAP (-17 ± 14 mmHg, -21 ± 17 mmHg, and -33 ± 20 mmHg, P < 0.05 versus vehicle for all; differences between groups not significant). Conclusion: In experimental CKD, AGT siRNA monotherapy appears to reduce proteinuria and heart weight in a blood pressure-independent fashion, to a similar degree as losartan or combination treatment. Thus, an siRNA targeting hepatic AGT may be a potential therapeutic approach for providing renal and cardioprotection in CKD.

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