Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease

et al. 2017

Hypertension

for the therapeutic potential of PGRN in hHcys-induced cardiorenal dysfunction, which was associated with the negative regulation of Wnt/β-catenin signaling. Materials and MethodsAn extended Materials and Methods section can be found in the online-only Data Supplement. AnimalsTwelve-week-old male PGRN-deficient (Grn −/− ) mice and wild-type C57BL/6 mice were purchased from the Jackson laboratory (Bar Harbor, ME).Abstract-Hyperhomocysteinemia (hHcys) is an important independent risk factor for the development of cardiovascular disease and end-stage renal disease. Although multiple approaches lowering the levels of homocysteine have been used in experimental studies and clinical trials, there is no effective therapy available to fully prevent homocysteineinduced injury. Therefore, identifying key molecules in the pathogenic pathways may provide clues to develop new therapeutic strategies for the treatment of hHcys-associated injury beyond lowering the plasma homocysteine levels. In this study, we found that the levels of progranulin (PGRN), an autocrine growth factor, were significantly reduced in the kidney and heart from a mouse model of hHcys. We further observed that in hHcys, PGRN-deficient mice significantly exacerbated cardiorenal injury as evidenced by higher levels of urinary albumin excretion, more severe renal morphological injuries, including pronounced glomerular basement membrane thickening and podocyte foot process effacement, and adverse myocardial remodeling versus wild-type mice. Mechanistically, we found that PGRNmedicated Wnt/β-catenin signaling was one of the critical signal transduction pathways that links homocysteine to cardiorenal injury. Importantly, we finally provided direct evidence for the therapeutic potential of PGRN in mice with hHcys by pretreatment with recombinant human PGRN. Collectively, our results suggest that PGRN may be an innovative therapeutic strategy for treating patients with hHcys. (Hypertension. 2017;69:259-266.

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Progranulin in Hyperhomocysteinemia-Induced Cardiorenal Dysfunction

Sun

et al. 2017

Hypertension

“…16 Interestingly, multiple RAS genes are novel targets of Wnt/b-catenin signaling, and blockade of b-catenin signaling by a small-molecule inhibitor is able to inhibit RAS and ameliorate kidney injury. 12 In harmony with this notion, renal b-catenin and its downstream target proteins such as Snail1, PAI-1, and MMP-7 are upregulated in diseased kidneys, 23,28,31,51,52 which is concurrent with RAS activation. Therefore, Wnt/b-catenin presumably functions as a mediator in coupling Klotho depletion with RAS activation in various CKD including aging-related nephropathy.…”

Section: Klotho Inhibits Rasmentioning

confidence: 93%

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

The American Journal of Pathology

Miao

et al. 2015

Self Cite

140

117

Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited b-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem, because it affects about 10% to 13% of the adult population worldwide.1e3 Among many risk factors for developing CKD, aging is an independent and strong predictor for progressive renal insufficiency. 4 The elderly population also tends to develop hypertension and cardiovascular disease, characteristic features consistent with the activation of the renin-angiotensin system (RAS). 5,6 These observations suggest that aging, CKD, and RAS activation might be intimately linked. However, the molecular details behind these connections are not fully understood.RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II type I and type II receptors (AT1 and AT2, respectively).7e9 Two main enzymes in this system, renin and ACE, lead to the formation of angiotensin II, the principal active peptide of RAS, which mediates both blood pressureedependent and eindependent kidney damage in CKD. Several factors can induce RAS activation, such as reactive oxygen species, hyperglycemia, and albumin. 10,11 We recently found that all RAS genes contain T cell factor/ lymphoid enhancer-binding factor binding sites in their promoter regions and are directly regulated by canonical Wnt/ b-catenin signaling.12 These results have established that bcatenin is a master regulator controlling the expression of all RAS components in the kidneys.

“…For example, Shh is known to upregulate Wnt2b and Wnt5a (Katoh and Katoh, 2009), as well as Notch ligand Jaggad2 (Katoh and Katoh, 2008). Wnts could induce Shh expression in epithelial cells, and both Wnt and Shh signaling can induce Snail1 expression in fibrotic kidneys (Ding et al, 2012; Wang et al, 2011; Zhou and Liu, 2015). Gli1 could induce Snail1 and promote β-catenin nuclear translocation in epithelial cells (Li et al, 2007).…”

Section: Targets and Mechanism Of Shh Signaling In Kidney Fibrosismentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Tan

Liu

2016

Sci. China Life Sci.

Self Cite

The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.