Rab7 empowers renal tubular epithelial cells with autophagy-mediated protection against albumin-induced injury.

Most patients with chronic kidney disease (CKD) present with proteinuria and extracellular matrix (ECM) deposition in the interstitium. Matrix metalloproteinase-2 (MMP-2) is important for maintaining ECM metabolism and it affects the formation and development of CKD. Autophagy has been reported to be protective against renal tubular injury, but the role of autophagy related to ECM metabolism is unclear. Rab7 is a shared molecule of endocytosis and autophagy. The aim of this study is to explore the role of autophagy in regulating MMP-2 activity and to determine whether Rab7 functions in regulating MMP-2 activity and injury in albumin-overloaded TECs. In this study, abovine serum albumin (BSA)-overload rat model was first established and collagen deposition and deficient autophagic response were observed in vivo, and stimulation with albumin nanoparticles resulted in MMP-2 overactivation and obstructed autophagic flux induced by lysosomal dysfunction in vitro. Furthermore, overactivation of MMP-2 was mediated by its related regulatory molecules such as membrane-type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase-2 (TIMP-2) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) on the membrane of TECs (HK-2 cellline). After up-regulating Rab7, albumin-induced MMP-2 overactivation was attenuated, which was reversed by chloroquine (CQ; an endocytosis inhibitor). In addition, our data indicated that up-regulation of Rab7 relieved epithelial-mesenchymal transition (EMT) and apoptosis in albumin-treated TECs. Taken together, our study demonstrated that autophagy regulates MMP-2 activity in a Rab7-dependent manner. Thus, Rab7 is a newly developed target for protecting TECs from albumin-induced injury.

An Attempt to Establish a Common Animal Model for Hepatorenal Fibrosis in Rats.

It is already a proven fact that there exists a relationship between CLD (chronic liver disease) and kidney disease but still there is no available combined animal model of liver and kidney fibrosis on the same animal. An animal model is one of the important research tools in the field of medical science because it is important to build a model that can simulate the disease condition so that the particular disease can be studied. Therefore, the aim of this study is to build a less expensive, less time consuming, and reproducible model of hepatorenal fibrosis on rats. We administered combined intraperitoneal injection of CCl4 (Carbon Tetrachloride) and BSA (Bovine Serum Albumin) on a female Wistar rats. At the end, the liver and kidney tissues were examined under microscope to see whether we were successful in establishing the model or not. The results show that liver fibrosis was marked but the changes on the kidneys were mild. In this study, we were able to induce significant fibrosis in the liver and early stages of fibrosis in the kidneys. The result also demonstrated that the addition of BSA conferred a liver protective effect against CCl4 induced hepatotoxicity, whereas combination of CCl4 and BSA proved to be detrimental for kidneys.

MMP-2 and 9 in Chronic Kidney Disease.

Gelatinases are members of the matrix metalloproteinase (MMPs) family; they play an important role in the degradation of the extracellular matrix (ECM). This effect is also crucial in the development and progression of chronic kidney disease (CKD). Its expression, as well as its activity regulation are closely related to the cell signaling pathways, hypoxia and cell membrane structural change. Gelatinases also can affect the development and progression of CKD through the various interactions with tumor necrosis factors (TNFs), monocyte chemoattractant proteins (MCPs), growth factors (GFs), oxidative stress (OS), and so on. Currently, their non-proteolytic function is a hot topic of research, which may also be associated with the progression of CKD. Therefore, with the in-depth understanding about the function of gelatinases, we can have a more specific and accurate understanding of their role in the human body.

A modified approach to establish a murine model of hypoxic renal interstitial fibrosis.

Modelling methods that are commonly used to establish a murine model of hypoxic renal interstitial fibrosis mainly includes 5/6 nephrectomy, unilateral ureteral obstruction and cyclosporin A (CsA)-induced renal interstitial fibrosis. The first two methods are technically challenging and unsuitable for clinical practice; thus, CsA induction is more promising. A previously introduced model of CsA-induced renal interstitial fibrosis involves the subcutaneous injection of CsA combined with a 0.01% low-sodium diet. The aim of this study was to provide a modified approach to this model by replacing the subcutaneous injection with gavage and the low-sodium diet with furosemide. From the gross morphology of kidney; the micro-specimens which were stained with haematoxylin-eosin (H&E), Masson-trichrome (Masson), periodic acid-Schiff (PAS); the renal function determination; and the expression of Vimentin protein. Our findings indicate that the combined administration of CsA every day and furosemide every other day by gavage at 80 mg/kg and 60 mg/kg, respectively, for 28 days can be used to successfully establish a murine model of renal interstitial fibrosis. Immunohistochemistry was used to show the expression of renin, the initiator of renin angiotensin aldosterone system (RAAS), while Western blotting was used to show the expression of hypoxia-inducible factor-1α (HIF-1α), a sensitive indicator of hypoxia. The expression levels of renin and HIF-1α revealed that RAAS activation and hypoxia are important mechanisms of this the model. Altogether, the data suggest that our modified approach is also an effective, alternative way to establish this model.