Abstract
Hyperuricemia, an independent risk factor for ensuing chronic kidney disease (CKD), contributed to tubulointerstitial fibrosis and insufficiency of renal fatty acid oxidation. Many studies have shown that renal fatty acid oxidation dysfunction is related to the TGF-β1/Smad3 signaling pathway. We experimented the effects of Zishen Qingre Tongluo Formula (ZQTF) on the adenine/yeast-induced HN rats and uric acid-induced renal mouse tubular epithelial cells (mTECs), determined whether this effect was related to the TGF-β1/Smad3 signaling pathway, and further investigated the relationship between this effect and renal fatty acid oxidation. Rats were given intraperitoneally with adenine (100 mg/kg) and feed chow with 10% yeast for 18 days and then received ZQTF (12.04 g/kg/day) via intragastric gavage for eight weeks. The TGF-β1/Smad3 signaling pathway and renal fatty acid oxidation protein were detected by using western blotting, real-time PCR, and immunohistochemistry staining. mTECs induced by UA were used to investigate the relationship between the TGF-β1/Smad3 signaling pathway and renal fatty acid oxidation. After treatment with ZQTF, levels of UA, 24 h UTP, BUN, and Scr were significantly decreased and histologic injuries were visibly ameliorated in HN rats. Western blotting, real-time PCR, and immunohistochemistry staining revealed that PGC-1α, PPARγ, and PPARα significantly increased, and fibronectin, collagen 1, and P-Smad3 significantly decreased in HN rats and UA-induced mTECs after ZQTF treatment. SIS3 (a specific inhibitor of Smad3) treatment significantly increased the expressions of PGC-1α, PPARγ, and PPARα and decreased the expressions of fibronectin, collagen 1, and P-Smad3 in UA-induced mTECs. Our study demonstrated that ZQTF exhibited renoprotective effects by promoting renal fatty acid oxidation via the regulation of the TGF-β1/Smad3 signaling pathway. Thus, the present results indicated that ZQTF was a novel antifibrotic strategy for hyperuricemic nephropathy.
Highlights
Uric acid (UA) is the ultimate product of purine metabolism, and 70% of UA is excreted via the kidneys in the urine [1]
After treatment with Zishen Qingre Tongluo Formula (ZQTF), levels of UA, 24 h UTP, blood urea nitrogen (BUN), and serum creatinine (Scr) were significantly decreased in hyperuricemic nephrology (HN) rats compared with levels in the untreated group
We found that specific inhibitor of Smad3 (SIS3) treatment significantly increased the expressions of PGC-1α, PPARγ, and PPARα and decreased the expressions of fibronectin, collagen 1, and P-Smad3 in UAinduced Mouse tubular epithelial cells (mTECs) (Figure 7(a) and 7(b))
Summary
Uric acid (UA) is the ultimate product of purine metabolism, and 70% of UA is excreted via the kidneys in the urine [1]. Epidemiological studies show that serum UA is enhanced in patients with chronic kidney disease (CKD) [2]. Considerable evidences highlight that chronic UA injury to the kidney is sufficient to trigger renal tubular injury, tubulointerstitial fibrosis, and glomerulosclerosis, leading to hyperuricemic nephrology (HN) [3]. Further exploration of the precise mechanism behind HN progression is urgently required. Of all these characters, renal interstitial fibrosis, the final common pathway of all progressive CKD, played a central role in HN [4]. Diseased proximal tubules play a critical role in interstitial fibrosis through the release of variety of autocrine and paracrine signals. Many different types of growth factors and cytokines regulated the renal
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