PhD student, Monash Univeristy
Kidneys are a essential organ in our body as it regulates our blood pressure, filters wastes, detoxifies blood and balances fluids. However there has been a 82% rise in chronic kidney diseases from just the past 2 decades globally. This is largely due to poor diet such as excessive salt consumption and less physical activity leading to obesity and high blood pressure. Patients often require organ transplant as a final measure and this can be very expensive thus effective drug therapies are needed.
One prime contributor to the progression of the kidney diseases is a process called fibrosis, where the kidneys are incorrectly healed and leaves rigid scarring which not only further kidney damage but also impedes on its ability to function correctly.
Hence, Imagine your kidneys are a football field and fibrosis (tissue scarring) is the ball. The left goal represents a healthy pair of kidneys whereas the right goal represents a damaged pair of kidneys. My job would be like the football manager, looking to find the right combination of players (drug treatments) to work effectively and efficiently at defending the ball from scoring to the left goal while attacking against the opposing players (factors that contribute to kidney damage).
Thus, my research involves the use of various current (Candesartan cilexetil, Perindorpil) and emerging (Relaxin, HFI-419) drug treatments to compare and combine their anti-fibrotic effects to see which are more effective at reversing scarring and restoring kidney functions in mice to hopefully be translated to restore normal kidney functions in patients suffering from chronic kidney damage in the future.
Abstract: To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis.Hepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting.Treatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels.The combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy.
Pub.: 28 Jun '17, Pinned: 31 Aug '17
Abstract: Recombinant H2 relaxin (serelaxin) has gained considerable attention as a new vasoprotective drug, largely due to its potential therapeutic effects in heart failure and fibrosis. However, serelaxin is laborious and costly to produce. A single-chain peptidomimetic, B7-33, has been developed to overcome these problems but little is known about its biological actions in the vascular system. This study first compared the rapid vascular effects of an acute bolus injection of B7-33 compared with serelaxin. Male Wistar rats received a tail vein injection of placebo (20mM sodium acetate), B7-33 (13.3μg/kg) or serelaxin (26.6μg/kg). Three hours later vascular function in the mesenteric artery, small renal artery and abdominal aorta was assessed by wire myography. B7-33 and serelaxin selectively enhanced bradykinin-mediated endothelium-dependent relaxation in the rat mesenteric artery by increasing endothelium-derived hyperpolarization, but had no overall effects on relaxation in the small renal artery or aorta. We then compared the actions of B7-33 and serelaxin in an ex vivo model of vascular disease using virgin female mouse mesenteric arteries pre-incubated in placental trophoblast conditioned media to induce endothelial dysfunction characteristic of preeclampsia. Co-incubation of these arteries in trophoblast conditioned media with B7-33 or serelaxin (15, 30nM) prevented the development of endothelial dysfunction. In conclusion, equimolar doses of B7-33 replicated the acute beneficial vascular effects of serelaxin in rat mesenteric arteries and also prevented endothelial dysfunction induced by placental trophoblast conditioned media in mouse mesenteric arteries. Therefore, B7-33 should be considered as a cost-effective vasoactive therapeutic in cardiovascular diseases, including preeclampsia.
Pub.: 10 May '17, Pinned: 31 Aug '17
Abstract: Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosis-related disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, anti-oxidant, anti-hypertrophic, anti-apoptotic, angiogenic, wound-healing and vasodilatory) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously-administered relaxin, and its mechanisms of action, that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic.
Pub.: 03 Jun '16, Pinned: 31 Aug '17
Abstract: Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.
Pub.: 07 Apr '17, Pinned: 31 Aug '17
Abstract: Renal fibrosis is a common feature of chronic kidney disease (CKD). To inhibit the CKD process, it is important to prevent renal fibrosis, though CKD remains incurable. Renal fibrosis can be inhibited by relaxin in several experimental models, but the mechanism of relaxin for antifibrotic potential is still not clear. And here we have studied the role of relaxin in macrophage polarization and renal inflammation after unilateral ureteral obstruction (UUO). Our results show that relaxin can downregulate the Toll-like receptor (TLR) 4 signaling, shift macrophage polarization toward the M2 phenotype and ameliorat renal fibrosis in the early stages of UUO. In vitro experiments, it has been confirmed that relaxin can downregulate the TLR4 signaling and induce the M2 macrophage transition. Furthermore, the transitional actions of macrophage phenotype induced by relaxin are significantly blocked by TAK-242, a TLR4 antagonist, in vitro experiments. Thus, there is a novel mechanism of relaxin for antifibrosis that shifts macrophage polarization toward the M2 phenotype via inhibition of TLR4 signaling.
Pub.: 19 Apr '17, Pinned: 31 Aug '17