scholarly journals Reduced Expression of Metallothionein-I/II in Renal Proximal Tubules Is Associated with Advanced Chronic Kidney Disease

Toxins ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 568
Author(s):  
Yi-Jhu Lu ◽  
Ya-Ju Wu ◽  
Lujen Chen ◽  
Bor-Sheng Ko ◽  
Tzu-Ching Chang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Manifestations ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Advanced Chronic Kidney Disease ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Hk2 Cells ◽  
Overall Mortality

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

scholarly journals Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ana B. Rodríguez-Peña ◽  
Isabel Fuentes-Calvo ◽  
Neil G. Docherty ◽  
Miguel Arévalo ◽  
María T. Grande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Akt Signaling ◽  
Small Gtpase ◽  
Tubulointerstitial Fibrosis ◽  
Ras Signaling ◽  
Signaling System ◽  
Ras Activation ◽  
Renal Tubulointerstitial Fibrosis

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, andα-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.

scholarly journals Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease

2020 ◽  
Vol 40 (5) ◽  
pp. 1239-1255 ◽  
Author(s):  
Nilaksh Gupta ◽  
Jennifer A. Buffa ◽  
Adam B. Roberts ◽  
Naseer Sangwan ◽  
Sarah M. Skye ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Functional Impairment ◽  
Tubulointerstitial Fibrosis ◽  
Intestinal Microbes ◽  
Renal Tubulointerstitial Fibrosis ◽  
Selective Targeting ◽  
The Impact

Objective: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. Conclusions: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.

Phosphate binders in patients with chronic kidney disease: Between the new and the old.

2019 ◽  
pp. 2-3
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Chronic Kidney Disease Stage ◽  
Disease Stage ◽  
Phosphate Binders ◽  
Advanced Chronic Kidney Disease ◽  
Phosphate Retention ◽  
Stage 4 ◽  
Dietary Phosphate

Impaired phosphate excretion by the kidney leads to Hyperphosphatemia. It is an independent predictor of cardiovascular disease and mortality in patients with advanced chronic kidney disease (stage 4 and 5) particularly in case of dialysis. Phosphate retention develops early in chronic kidney disease (CKD) due to the reduction in the filtered phosphate load. Overt hyperphosphatemia develops when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m2. Hyperphosphatemia is typically managed with oral phosphate binders in conjunction with dietary phosphate restriction. These drugs aim to decrease serum phosphate by binding ingested phosphorus in the gastrointestinal tract and its transformation to non-absorbable complexes [1].

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