Blocking ribosomal protein S6 phosphorylation inhibits podocyte hypertrophy and focal segmental glomerulosclerosis

Abstract

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion. Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion. Translational StatementAlthough recent studies have suggested that maladaptive podocyte hypertrophy might cause progressive podocyte depletion leading to focal segmental glomerulosclerosis (FSGS), the underlying mechanism remains to be demonstrated in detail. In the present study, we observed marked increases of phosphorylated ribosomal protein S6 (p-rpS6) in the renal glomeruli of FSGS patients, as well as in Adriamycin-induced FSGS mice, in which excessive podocyte hypertrophy was detected. We report the first genetic and pharmacologic evidence indicating that targeting substrate S6 kinase 1 (S6K1)–mediated rpS6 phosphorylation inhibits podocyte hypertrophy, prevents podocyte depletion, and attenuates FSGS. Our results demonstrate that targeting rpS6 phosphorylation could be an effective therapeutic strategy to treat podocytopathies such as FSGS. This report should stimulate development of small-molecule inhibitors specific for rpS6 phosphorylation, so that individualized dose-dependent therapy can minimize any potential adverse effects. Although recent studies have suggested that maladaptive podocyte hypertrophy might cause progressive podocyte depletion leading to focal segmental glomerulosclerosis (FSGS), the underlying mechanism remains to be demonstrated in detail. In the present study, we observed marked increases of phosphorylated ribosomal protein S6 (p-rpS6) in the renal glomeruli of FSGS patients, as well as in Adriamycin-induced FSGS mice, in which excessive podocyte hypertrophy was detected. We report the first genetic and pharmacologic evidence indicating that targeting substrate S6 kinase 1 (S6K1)–mediated rpS6 phosphorylation inhibits podocyte hypertrophy, prevents podocyte depletion, and attenuates FSGS. Our results demonstrate that targeting rpS6 phosphorylation could be an effective therapeutic strategy to treat podocytopathies such as FSGS. This report should stimulate development of small-molecule inhibitors specific for rpS6 phosphorylation, so that individualized dose-dependent therapy can minimize any potential adverse effects. Focal segmental glomerulosclerosis (FSGS) is a pathologic diagnosis referring to a histologic pattern of kidney injury characterized by sclerotic lesions in glomeruli that are focal and segmental, as shown by light microscopy.1Jefferson J.A. Shankland S.J. The pathogenesis of focal segmental glomerulosclerosis.Adv Chronic Kidney Dis. 2014; 21: 408-416Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 2Wharram B.L. Goyal M. Wiggins J.E. et al.Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.J Am Soc Nephrol. 2005; 16: 2941-2952Crossref PubMed Scopus (560) Google Scholar, 3Kim Y.H. Goyal M. Kurnit D. et al.Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat.Kidney Int. 2001; 60: 957-968Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar Regardless of the initial etiologies, glomerular podocyte injury–induced podocyte depletion increasingly has been recognized to be a common, and the most critical, cellular mechanism driving progression of FSGS.1Jefferson J.A. Shankland S.J. The pathogenesis of focal segmental glomerulosclerosis.Adv Chronic Kidney Dis. 2014; 21: 408-416Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 2Wharram B.L. Goyal M. Wiggins J.E. et al.Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.J Am Soc Nephrol. 2005; 16: 2941-2952Crossref PubMed Scopus (560) Google Scholar, 3Kim Y.H. Goyal M. Kurnit D. et al.Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat.Kidney Int. 2001; 60: 957-968Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 4Matsusaka T. Xin J. Niwa S. et al.Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.J Am Soc Nephrol. 2005; 16: 1013-1023Crossref PubMed Scopus (201) Google Scholar, 5Wiggins R.C. The spectrum of podocytopathies: a unifying view of glomerular diseases.Kidney Int. 2007; 71: 1205-1214Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar, 6D'Agati V.D. Kaskel F.J. Falk R.J. Focal segmental glomerulosclerosis.N Engl J Med. 2011; 365: 2398-2411Crossref PubMed Scopus (530) Google Scholar, 7Zhong J. Whitman J.B. Yang H.C. Fogo A.B. Mechanisms of scarring in focal segmental glomerulosclerosis.J Histochem Cytochem. 2019; 67: 623-632Crossref PubMed Scopus (4) Google Scholar To date, FSGS remains a major cause of nephrotic syndrome and a leading cause of end-stage kidney disease globally, including in the US.8Rosenberg A.Z. Kopp J.B. Focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2017; 12: 502-517Crossref PubMed Scopus (216) Google Scholar Further research into the molecular mechanisms underlying progressive podocyte depletion may lead to the development of therapeutic strategies for the prevention of FSGS progression to end-stage kidney disease. The mechanism underlying podocyte loss has been debated. Previous observations suggest that podocyte detachment as viable cells, rather than in situ apoptosis or necrosis, is the major mechanism of podocyte loss in many cases.9Fukuda A. Chowdhury M.A. Venkatareddy M.P. et al.Growth-dependent podocyte failure causes glomerulosclerosis.J Am Soc Nephrol. 2012; 23: 1351-1363Crossref PubMed Scopus (123) Google Scholar,11Bhathena D.B. Glomerular basement membrane length to podocyte ratio in human nephronopenia: implications for focal segmental glomerulosclerosis.Am J Kidney Dis. 2003; 41: 1179-1188Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Of note, the terminally differentiated podocytes in adult kidneys have very limited capability to proliferate, but they can cellular hypertrophy to for a podocyte to podocyte loss or glomerular The of podocyte hypertrophy might have an or maladaptive podocyte hypertrophy cause and in progressive podocyte leading to the development and progression of A. Chowdhury M.A. Venkatareddy M.P. et al.Growth-dependent podocyte failure causes glomerulosclerosis.J Am Soc Nephrol. 2012; 23: 1351-1363Crossref PubMed Scopus (123) Google J.E. Goyal M. et al.Podocyte hypertrophy, and associated with glomerular and glomerulosclerosis in the prevention by Am Soc Nephrol. 2005; 16: PubMed Scopus Google Scholar, et of podocytes from the glomerular basement membrane hypertrophic 2014; PubMed Scopus Google Scholar, signaling in and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar hypertrophy is characterized by growth resulting in increased and The mammalian target of rapamycin is a protein kinase in mammalian that by complex 1 and J. et signaling kidney PubMed Scopus Google Scholar Previous studies that the growth receptor and the phosphatase of phosphatase and the of the kidneys the signaling J. R.C. of mammalian target of rapamycin signaling in renal Am Soc Nephrol. 2005; 16: PubMed Scopus Google Scholar In renal hypertrophy is by of the kinase 1 signaling J. 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Venkatareddy M.P. et podocyte loss from glomeruli causes progression of kidney Int. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar human and evidence that podocyte depletion causes the development and progression of et of podocytes from the glomerular basement membrane hypertrophic 2014; PubMed Scopus Google A. Venkatareddy M.P. et podocyte loss from glomeruli causes progression of kidney Int. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar the that podocytes are via detachment from the glomerular basement membrane as viable cells, and in the M. et to the of J PubMed Scopus Google Scholar, potential role for in the detachment of podocytes and the progression of Am Soc Nephrol. PubMed Scopus Google Scholar, The role of target of rapamycin in of glomerular PubMed Scopus Google Scholar studies suggest that podocyte hypertrophy may be a major cause of podocyte D.B. Glomerular basement membrane length to podocyte ratio in human nephronopenia: implications for focal segmental glomerulosclerosis.Am J Kidney Dis. 2003; 41: 1179-1188Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Previous studies that of the hypertrophy of renal proximal by rpS6 phosphorylation and cellular protein J. R.C. of mammalian target of rapamycin signaling in renal Am Soc Nephrol. 2005; 16: PubMed Scopus Google Scholar, J. et kinase 1 inhibits or renal J PubMed Scopus Google Scholar, J. J. et of ribosomal protein S6 mediates renal Int. Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. et of kinase the of J PubMed Scopus Google Scholar, T. J. et of inhibits the hypertrophic growth of renal proximal tubule PubMed Scopus Google Scholar, R.J. T. et but by the PubMed Scopus Google Scholar In study, we observed an increased of in the podocytes of kidney from FSGS We observed increased rpS6 phosphorylation in podocytes of FSGS mice. results that the is activated in the podocytes with FSGS. of is that is significantly activated in podocytes during kidney but the of signaling is very in podocytes et of a and specific inhibitor of ribosomal S6 kinase J. 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This is with a report that of rapamycin Wiggins J.E. Goyal M. et of a and for of podocyte glomerular and glomerular podocyte in kidney with protein as a podocyte Am Soc Nephrol. 2003; PubMed Scopus Google Scholar In to protein 1 is substrate of which has phosphorylation in mammalian J. et signaling kidney PubMed Scopus Google the of and 21: PubMed Scopus Google Scholar However, phosphorylation of has been demonstrated to control but J. J. et rpS6 phosphorylation kidney Am Soc Nephrol. 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Goyal M. et of a and for of podocyte glomerular and glomerular podocyte in kidney with protein as a podocyte Am Soc Nephrol. 2003; PubMed Scopus Google Scholar results evidence for individualized to treat FSGS progression in and they that is to the of the targeting of or of that are for podocyte and and cause glomerular than be a rpS6 is in signaling that et podocyte and apoptosis by Dis. 2019; PubMed Scopus Google M. A. et in ribosomal protein S6 phosphorylation from that a growth and PubMed Scopus Google Scholar the in our present study rpS6 we mice with a pharmacologic inhibitor of protein phosphatase which is known to negatively regulate rpS6 T. et protein S6 phosphorylation is a of and 2005; PubMed Scopus Google V.D. of focal segmental glomerulosclerosis: 2012; 21: PubMed Scopus Google Scholar Our results that the pharmacologic of protein phosphatase 1 in an of of rpS6 This of protein a of podocyte hypertrophy that podocyte depletion, leading to FSGS lesions and with levels of and is a major kinase that and the inhibitor has been demonstrated to rpS6 J. J. and of in to PubMed Scopus Google Scholar We and found that treatment inhibited rpS6 phosphorylation in mice. This signaling blunted podocyte hypertrophy, podocyte loss, attenuated FSGS and kidney pharmacologic suggest that an of in podocytes a pathologic role in the development and progression of FSGS. To such a role of rpS6 phosphorylation a genetic mouse we into rpS6 knock-in mice, in which non-phosphorylatable rpS6 and rpS6 phosphorylation with our from pharmacologic our genetic that with rpS6 blocking rpS6 phosphorylation attenuated podocyte hypertrophy, inhibited podocyte loss, FSGS and kidney in mice. The present study provides evidence that rpS6 an role in podocyte hypertrophy and podocyte depletion in an mouse model of FSGS. is the podocyte injury and In to podocyte hypertrophy, the apoptosis of J. et of podocyte apoptosis and disease progression in Adriamycin-induced focal segmental PubMed Scopus Google Scholar and resulting from in podocytes of FSGS mice, and podocyte J.A. a target for therapy of focal segmental glomerulosclerosis.Am J Nephrol. PubMed Scopus Google Scholar leading to a of podocytes that was to the of rpS6 In the study that is in FSGS patients and mouse of FSGS. Using pharmacologic approaches and genetic mouse our that levels of can cause excessive hypertrophy of leading to podocyte depletion and segmental glomerulosclerosis. or blocking rpS6 phosphorylation to podocyte hypertrophy can attenuate podocyte depletion and FSGS lesions. Thus, our results suggest that specifically targeting rpS6 phosphorylation is an effective therapeutic strategy for the prevention and treatment of FSGS via prevention of excessive podocyte hypertrophy and progressive podocyte depletion. the The of has been for the of for This be in Kidney and This was by the of The role in study or to or of the with In disease results from a of the leading to of in cells, including the disease is are and podocytes have the of podocytes in may be or a of patients with disease to kidney and a for of the in podocytes of patients and they to demonstrate that with podocyte increased and with podocyte with PDF

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