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Four-And-A-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease

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Four-And-A-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease BASIC RESEARCH www.jasn.org Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease † ‡ | Szu-Yuan Li,* Po-Hsun Huang, Der-Cherng Tarng, Tzu-Ping Lin,§ Wu-Chang Yang, | †† Yen-Hwa Chang,§ An-Hang Yang,¶ Chih-Ching Lin, Muh-Hwa Yang,** Jaw-Wen Chen, ‡‡ || †† Geert W. Schmid-Schönbein, Shu Chien,§§ Pao-Hsien Chu, and Shing-Jong Lin Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/b-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-b1, activated FHL2 protein and Wnt/b-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/b-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2+/+ mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2+/+ mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with di- abetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both struc- tural and functional protein-protein interactions with b-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/b-catenin–induced podocytopathy. J Am Soc Nephrol 26: 3072–3084, 2015. doi: 10.1681/ASN.2014100989 Diabetic kidney disease (DKD) is the leading cause glomerular filtration barrier. Podocytes are highly of ESRD, affecting 10%–40% of diabetic patients, specialized, terminally differentiated cells that can- and the cost of RRT remains a large economic bur- not proliferate.2 Recently, hyperactive podocyte den for the health care system. Proteinuria is a major and primary clinical aspect of DKD and causes Received October 13, 2014. Accepted February 23, 2015. tubulointerstitial lesions that lead to renal dysfunc- 1 Published online ahead of print. Publication date available at tion. Reducing proteinuria may therefore be a princi- www.jasn.org. pal therapeutic target to improve renal outcome in patients with DKD. However, the pathophysiologic Correspondence: Dr. Po-Hsun-Huang, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and mechanism of DKD is multifactorial, and some patients Institute of Clinical Medicine, and Cardiovascular Research develop treatment-resistant proteinuria that results in Center, National Yang-Ming University, No 201, Sec 2, SHih-Pai ESRD despite intensive BP and glycemia control. Thus, Road, Taipei, Taiwan, or Dr. Pao-Hsien Chu, Division of Cardi- fi ology, Department of Internal Medicine; Healthcare Center; identi cation of major DKD mechanisms and develop- Heart Failure Center, Chang Gung Memorial Hospital, Chang ment of new therapeutic options are needed. Gung University, College of Medicine, Taipei, Taiwan. Email: Glomerularepithelial cells, also calledpodocytes, [email protected] or [email protected] are predominantly responsible for maintaining the Copyright © 2015 by the American Society of Nephrology 3072 ISSN : 1046-6673/2612-3072 JAmSocNephrol26: 3072–3084, 2015 www.jasn.org BASIC RESEARCH Wnt/b-catenin signaling has been shown to play an essential RESULTS role in the development of DKD. The Wnt family of signaling proteins participates in multiple developmental events during FHL2 Is Abundantly Expressed in Mature Podocytes embryogenesis and has been implicated in adult tissue homeo- We used three different methods to identify the expression and stasis. Wnt signals modulate pleiotropic effects, such as in- distribution of FHL2 in kidney tissues. In human kidney clude mitogenic stimulation and cell-fate specification. samples, immunohistochemical (IHC) staining with a mono- An important component of the Wnt pathway is b-catenin, clonal antibody showed that FHL2 is highly expressed in which resides in the cytoplasm in a multiprotein complex. glomerular cells (Figure 1, A and B). We further used immu- One component of this complex, glycogen synthase kinase 3 nofluorescence double-staining and confirmed that FHL2 is (GSK3), phosphorylates b-catenin in the absence of Wnt abundantly expressed in podocytes (Figure 1C, Supplemental signaling, and phosphorylated b-catenin is subsequently Material). To avoid the potential antibody cross-reactivity in ubiquitinated and degraded via proteasomes. Upon Wnt sig- IHC staining, we introduced the LacZ gene in the FHL2 locus naling stimulation, b-catenin is stabilized and translocated by homologous recombination, and LacZ staining confirmed to the cell nucleus. As a transcriptional activator, b-catenin that FHL2 is expressed in mouse glomeruli (Figure 1D). binds the transcription factor of T cell–specific transcription A previous report demonstrated that cultured human podocytes factor (TCF) in the cell nucleus and starts target gene transcrip- have abundant FHL2 mRNA expression in nonpermissive tion.3,4 In clinical studies, aberrant Wnt signaling has been shown conditions.25 Here, we used Western blot to demonstrate to be responsible for various malignant and metabolic diseases.5–8 thatFHL2proteinexpressionismodestinthepermissivepro- As a developmental signaling pathway, the Wnt/b-catenin liferating stage but becomes abundant in nonpermissive well system is essentially silenced in differentiated podocytes, but differentiated podocytes (Figure 1E). activated Wnt/b-catenin signaling has been found in various types of proteinuric kidney disease,9–11 particularly in Diabetes Mellitus–Related Cytokines Activate the Wnt DKD.10,12,13 Wnt/b-catenin is a key element of podocyte dys- Pathway and Upregulate FHL2 Expression in Human function by downregulating nephrin via a Snail-dependent Podocytes mechanism.10 Target inhibition of podocyte Wnt signaling To investigate the effect of high glucose conditions and does not alter kidney microstructure and function but pre- diabetes-related cytokines on FHL2 regulation, differentiated vents podocytopathy in doxorubicin- induced nephropathy.10 human podocytes were exposed to various stimulators. As On the contrary, activation of b-catenin in podocytes results shown in Figure 2, A and B, high glucose, TGF-b,andangio- in podocyte foot process effacement, glomerular basement tensin II stimulate Wnt/b-catenin signaling in podocytes. membrane (GBM) thickening, and significant albumin- Western blot revealed increased active b-catenin protein level, uria,14 implying that the Wnt pathway is not necessary for and importantly, that these stimulators also upregulated FHL2 normal podocyte function, but its activation during renal in- protein expression. The GSK-3 inhibitor, a direct Wnt path- jury might reflect a harmful signaling. way activator, markedly increased active b-catenin but did not The LIM domain is a cysteine-rich motif that has been pro- affect FHL2 protein expression, which suggests FHL2 is not a posed to direct protein-protein interaction. A diverse group of Wnt targeted–protein. proteins containing LIM domains have been identified, which Several groups have addressed the possibility that various display various functions.15 A concept is emerging that the LIM stimuli modulate subcellular distribution of FHL2. To domains can associate with both the actin cytoskeleton and the explore and test this hypothesis in podocytes, we used transcriptional machinery. The functions of LIM domain pro- nuclear/cytoplasmic protein extraction and immunofluo- teins in the nucleus are mainly in tissue-specificgeneregulation, rescencestaining to evaluateFHL2 subcellulardistributionin whereas cytoplasmic LIM domain proteins are mainly involved cultured podocytes. Under normal culture conditions, FHL2 in cytoskeleton organization.16 Four-and-a-half LIM domains was mainly expressed in podocyte cytosol, located on the protein (FHL) contains four-and-a-half LIM domain–binding podocyte cytoskeleton, and translocated to the cell nucleus proteins. Proteins in this family function as adaptors or scaffolds after stimulation by high glucose and diabetes mellitus to support the assembly of metameric protein complexes for (DM)–related cytokines (Figure 2C). The b-catenin was dis- critical cellular processes.17 The best-studied member of this tributed in the cell-cell junction, and no protein-protein family, FHL2, is highly expressed in cardiovascular and urogenital interactions were found between FHL2 and b-catenin under systems. The role of FHL2 has been investigated intensively in normal conditions. However, under high glucose condi- cardiovascular diseases over the past
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