Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

Abstract

Renal fibrosis is a common feature of chronic kidney disease and is a promising therapeutic target. However, there is still limited treatment for renal fibrosis, so the development of new anti-fibrotic agents is urgently needed. Accumulating evidence suggest that oxidative stress and endoplasmic reticulum (ER) stress play a critical role in renal fibrosis. Carnosol (CS) is a bioactive diterpene compound present in rosemary plants and has potent antioxidant and anti-inflammatory properties. In this study, we investigated the potential effects of CS on renal injury and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice underwent sham or UUO surgery and received intraperitoneal injections of CS (50 mg/kg) daily for 8 consecutive days. CS improved renal function and ameliorated renal tubular injury and interstitial fibrosis in UUO mice. It suppressed oxidative injury by inhibiting pro-oxidant enzymes and activating antioxidant enzymes. Activation of ER stress was also attenuated by CS. In addition, CS inhibited apoptotic and necroptotic cell death in kidneys of UUO mice. Furthermore, cytokine production and immune cell infiltration were alleviated by CS. Taken together, these findings indicate that CS can attenuate renal injury and fibrosis in the UUO model.

Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

“…Our data validated that CAD could restore the activity of crucial antioxidant enzymes to block oxidative stress in both I/R and UUO models. In addition, the influential outcome of SOD1, catalase, and SOD2 on alleviating acute and chronic injuries was authenticated as well in our reports and others. , …”

“…In agreement with tissue staining, specific kidney injury markers such as BUN and Cr also experienced a noticeable decline in the UUO + CAD group (Figure H,I). Additionally, positive indicators of fibrosis degree including collagen I, collagen III, fibronectin, and α-SMA went through the conspicuous upregulation in the UUO surgery . Nevertheless, CAD delivery by gavage reversed the alteration trend of protein expression in those markers (Figure J).…”

“…Destructive or persistent pathological circumstances stimulated the unrestrained formation of ROS, leading to harmful disturbance on antioxidative defense and distinguished repression of antioxidant enzymes (SOD, CAT, etc. ). , Excessive and permanent OS inevitably triggered renal cell death by intensifying endoplasmic reticulum stress, pyroptosis, and apoptosis as testified by our published studies. ,,, However, the regulatory mechanisms of oxidative stress in AKI or CKD are not absolutely identical despite the crucial participation of OS. ,− In recent years, relevant studies frequently demonstrated that suppressing OS would be capable of ameliorating renal fibrosis or AKI to a large extent. − Therefore, identifying and targeting the common pathways or molecules seem to be promising and necessary for treating kidney diseases. , Hopefully, some of the antioxidants and anti-inflammation regents have already been tested in clinical trials in patients with relevant kidney diseases and have exhibited encouraging end results. For example, Pablo E Pergola and his colleagues discovered that the oral administration of bardoxolone methyl, one modulator of antioxidant and anti-inflammation, upgraded the estimated glomerular filtration rate in patients along with type 2 diabetes and CKD at 24 weeks .…”

“…In response to various kinds of stress, inflammatory factors such as TNF-α, IL-6, and Il-1β would be secreted to regulate local tissue and systemic reactions . Inflammation is involved in multiple renal diseases induced by AKI or CKD and is implicated to be a meaningful and potential therapeutic target. ,,,, As mentioned above, a number of anti-inflammation agents have been practiced in clinical trials for kidney diseases with some success. According to prior reports, CAD has powerful anti-inflammatory properties in alleviating LPS-induced septic shock, osteoarthritis, colitis, and carrageenan-induced paw edema via inhibiting inflammatory factors, MAPK, and NF-κB signaling pathways. ,,, In agreement with those findings, CAD occupied a crucial part in mitigating inflammatory cytokines consisting of TNF-α, IL-6, and Il-1β induced by UUO and I/R damage.…”

Antioxidant, Antiapoptotic, and Anti-Inflammatory Effects of Hesperetin in a Mouse Model of Lipopolysaccharide-Induced Acute Kidney Injury

“…However, hesperetin treatment alleviated LPS-induced renal tubular structural damages (tubular injury score: LPS, 2.4 ± 0.3 vs. LPS+Hes, 1.1 ± 0.2, p < 0.01; Figure 1 B,C). Next, the brush border of proximal tubules was visualized using a fluorescein isothiocyanate (FITC)-conjugated lotus tetragonolobus lectin (LTL) to examine the brush border loss [ 26 , 27 ]. Immunofluorescence (IF) staining revealed that LPS injection reduced the percentage of the LTL-stained area, but this change was mitigated by hesperetin (LPS, 4.1 ± 1.0% vs. LPS+Hes, 9.1 ± 1.4%, p < 0.05; Figure 1 D,E).…”