Renal fibrosis: New insights into the pathogenesis and therapeutics

Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease. The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. In a simplistic view, renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury. Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial–mesenchymal transition, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions. Among the many fibrogenic factors that regulate renal fibrotic process, transforming growth factor-β (TGF-β) is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated. Recent discoveries on endogenous antifibrotic factors have evolved novel strategies aimed at antagonizing the fibrogenic action of TGF-β/Smad signaling. Many therapeutic interventions appear effective in animal models; however, translation of these promising results into humans in the clinical setting remains a daunting task. This mini-review attempts to highlight the recent progress in our understanding of the cellular and molecular pathways leading to renal fibrosis, and discusses the challenges and opportunities in developing therapeutic strategies

Sequential Wnt Agonist then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis

Tissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury, and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that Wnt-mediated memory of prior injury contributes to fibrosis progression, and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries

The Many Faces of Matrix Metalloproteinase-7 in Kidney Diseases

Matrix metalloproteinase-7 (MMP-7) is a secreted zinc-dependent endopeptidase that is implicated in regulating kidney homeostasis and diseases. MMP-7 is produced as an inactive zymogen, and proteolytic cleavage is required for its activation. MMP-7 is barely expressed in normal adult kidney but upregulated in acute kidney injury (AKI) and chronic kidney disease (CKD). The expression of MMP-7 is transcriptionally regulated by Wnt/β-catenin and other cues. As a secreted protein, MMP-7 is present and increased in the urine of patients, and its levels serve as a noninvasive biomarker for predicting AKI prognosis and monitoring CKD progression. Apart from degrading components of the extracellular matrix, MMP-7 also cleaves a wide range of substrates, such as E-cadherin, Fas ligand, and nephrin. As such, it plays an essential role in regulating many cellular processes, such as cell proliferation, apoptosis, epithelial-mesenchymal transition, and podocyte injury. The function of MMP-7 in kidney diseases is complex and context-dependent. It protects against AKI by priming tubular cells for survival and regeneration but promotes kidney fibrosis and CKD progression. MMP-7 also impairs podocyte integrity and induces proteinuria. In this review, we summarized recent advances in our understanding of the regulation, role, and mechanisms of MMP-7 in the pathogenesis of kidney diseases. We also discussed the potential of MMP-7 as a biomarker and therapeutic target in a clinical setting

A Fast Independent Component Analysis Algorithm for Geochemical Anomaly Detection and Its Application to Soil Geochemistry Data Processing

A fast independent component analysis algorithm (FICAA) is introduced to process geochemical data for anomaly detection. In geochemical data processing, the geological significance of separated geochemical elements must be explicit. This requires that correlation coefficients be used to overcome the limitation of indeterminacy for the sequences of decomposed signals by the FICAA, so that the sequences of the decomposed signals can be correctly reflected. Meanwhile, the problem of indeterminacy in the scaling of the decomposed signals by the FICAA can be solved by the cumulative frequency method (CFM). To classify surface geochemical samples into true anomalies and false anomalies, assays of the 1 : 10 000 soil geochemical data in the area of Dachaidan in the Qinghai province of China are processed. The CFM and FICAA are used to detect the anomalies of Cu and Au. The results of this research demonstrate that the FICAA can demultiplex the mixed signals and achieve results similar to actual mineralization when 85%, 95%, and 98% are chosen as three levels of anomaly delineation. However, the traditional CFM failed to produce realistic results and has no significant use for prospecting indication. It is shown that application of the FICAA to geochemical data processing is effective

Klotho-derived peptide KP1 ameliorates SARS-CoV-2-associated acute kidney injury

Introduction: The severe cases of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often present with acute kidney injury (AKI). Although old age and preexisting medical conditions have been identified as principal risk factors for COVID-19-associated AKI, the molecular basis behind such a connection remains unknown. In this study, we investigated the pathogenic role of Klotho deficiency in COVID-19-associated AKI and explored the therapeutic potential of Klotho-derived peptide 1 (KP1).Methods: We assessed the susceptibility of Klotho deficient Kl/Kl mice to developing AKI after expression of SARS-CoV-2 N protein. The role of KP1 in ameliorating tubular injury was investigated by using cultured proximal tubular cells (HK-2) in vitro and mouse model of ischemia-reperfusion injury (IRI) in vivo.Results: Renal Klotho expression was markedly downregulated in various chronic kidney disease (CKD) models and in aged mice. Compared to wild-type counterparts, mutant KL/KL mice were susceptible to overexpression of SARS-CoV-2 N protein and developed kidney lesions resembling AKI. In vitro, expression of N protein alone induced HK-2 cells to express markers of tubular injury, cellular senescence, apoptosis and epithelial-mesenchymal transition, whereas both KP1 and Klotho abolished these lesions. Furthermore, KP1 mitigated kidney dysfunction, alleviated tubular injury and inhibited apoptosis in AKI model induced by IRI and N protein.Conclusion: These findings suggest that Klotho deficiency is a key determinant of developing COVID-19-associated AKI. As such, KP1, a small peptide recapitulating Klotho function, could be an effective therapeutic for alleviating AKI in COVID-19 patients

Relationship between Non-Pathogenic Bacteria from Eggs of Healthy Laying Ducks and Flora Structure in the Genital Tract and Cecum

Objective: The aim was to investigate whether a bacterial flora exists in the eggs of healthy laying ducks (Ma breed), and if yes, whether the bacterial flora could be associated with those in the genital tract and cecum. Methods: Healthy laying ducks were dissected to collect genital tract and cecum tissues, as well as soft- and hard-shelled duck eggs, and cultivable bacteria were counted by plate count method, and the diversity and correlation of uncultured bacterial flora were analyzed by MiSeq high-throughput sequencing. Results: The decreasing order of the total bacterial counts in the samples was cecum > genital tract > hard-shelled egg > soft-shelled egg. The bacterial gene sequences belonged to 56 phyla and 1 319 genera. The abundance and species evenness of bacteria in the cecum and genital tract were higher. The dominant genera included Bacteroides, Megamonas and Campylobacter. Species abundance and dominant concentration were higher in soft- and hard-shell eggs. Pseudomonas and Acinetobacter accounted for 19.01% and 10.01% of the total abundance, respectively. Gene function prediction showed that all samples had high abundance of metabolic and glycolytic functions. The gram-positive and anaerobic phenotypes in the cecum and genital tract were abundant. The pathogenicity and oxidative stress of bacteria in soft and hard shell eggs were significant. The dominant bacterial genera in the four samples were overlapped, and the overlap rates of egg content with the cecum and genital tract were 13.96% and 24.35%, respectively. In addition, the phylogenetic tree analysis showed that the genera in all samples were closely related to each other and shared homology with the significantly contributing genus Bacteroides in the cecum. Conclusion: Duck eggs are not formed in a sterile environment, the bacteria residing in the cecum and reproductive tract of healthy laying ducks can infect different egg structures during its formation and become a part of the internal flora in duck eggs. These results can provide a reference for further research on the characteristics and control of non-pathogenic bacteria in egg contents