Madhav Menon, MBBS, MD
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Research Summary
Many patients with chronic kidney disease (CKD) will progress, and many patients with a kidney transplant will experience allograft loss in the long term. There is an urgent need to understand mechanisms of disease progression in native and allograft kidneys, in order to design novel therapeutics. Genome-wide association studies (GWAS) have identified candidate susceptibility loci for CKD. The mechanistic basis of GWAS-variant associations with CKD are largely undescribed. The model our lab pursues is to use genetic data from human cohorts to identify clearly relevant loci and genes, and apply in vitro /in vivo models to study mechanism. Our studies are funded by the NIH and the DOD.
Extensive Research Description
1. By histology in native and allograft kidneys, CKD is characterized by renal interstitial fibrosis, vascular intimal fibrosis and glomerulo- sclerosis, reflecting damage to different renal compartments. We previously showed that a CKD-associated SHROOM3 SNP - Rs17319721, in the donor kidney increased SHROOM3 expression (by TCF7L2-dependent transcription) and promoted renal allograft fibrosis (IF/TA), through TGF-β1 signaling. These data contrast with evidence of a protective role for Shroom3 in glomerular development and association of this SNP with reduced albuminuria. To study mechanism of these dichotomous effects, we have developed inducible Shroom3 knockdown mice and observed reduced renal fibrosis with non-glomerular Shroom3 knockdown. Conversely, glomerular-, but not tubular-Shroom3 knockdown, induced albuminuria with diffuse podocyte foot process effacement without podocyte loss. In podocytes, we identified a new interaction of SHROOM3 with FYN (a Src kinase) via a critical Src homology-3 binding domain, distinct from its established domains. In vitro and in vivo, Shroom3-Fyn interaction was required for activation of Fyn kinase and downstream Nephrin phosphorylation and actin cytoskeleton in podocytes and explains the protective effect of Shroom3 on proteinuria. We are testing the dichotomous roles of Shroom3 in renal tubular cells and podocytes, that are mediated by distinct protein motifs. We have generated ASD2- domain deficient Shroom3 mutants to confirm ASD2-domain dependent profibrotic signaling by Shroom3, while Fyn-binding mutant Shroom3 will be overexpressed to confirm podocyte injury and phenotype in vivo. This work is focused on targeting Shroom3 for fibrosis in CKD and IF/TA.
2. Podocyte AMPK-signaling- Translating discoveries to humans: The phenotype of Shroom3 knockdown is similar to human minimal change disease (MCD) which has good prognosis vs FSGS (podocyte loss and sub-optimal prognosis). Since impaired Fyn activation is associated with human MCD, and Shroom3 knockdown inhibited Fyn , we evaluated whether collateral signaling mechanisms downstream of Fyn promoted podocyte survival. We identified enhanced AMPK-activation downstream of Shroom3-Fyn as a key prosurvival mechanism. Based on the widely used and safe AMPK-activator Metformin, and our mechanistic our group has designed a RCT (clinical trial) to test utility of Metformin to promote podocyte survival in FSGS. Analogously unique mouse models have been developed to understand mechanisms of podocyte survival downstream of AMPK including autophagy.
3. APOL1 variants and kidney injury: While Americans of African ancestry make up 13% of the United States, they account for 35% of kidney failure. This is attributed to the carriage of risk alleles in APOL1 (referred to G1/G2 risk alleles). Unfortunately, those with APOL1 risk variants manifest with FSGS, which is the most common form of nephrotic syndrome. However, limited mechanistic understanding of this disease process has hindered novel treatments, especially due to the lack of suitable animal models for study. With Dr Ishibe, we have a mouse model that expresses human APOL1 risk alleles. Upon stimulation with an inflammatory agent, these mice develop excessive protein loss in the urine resembling human FSGS. Using data in humans, we identified for the first time that immune cells, in addition to kidney cells, may play a profound role in disease processes including kidney transplant rejection. We propose that specific immune cells in individuals with G1/G2 APOL1 damage the kidney filtration barrier (in native kidneys) or promote rejection (in transplants). We focus on studying APOL1-variant carrying T-cells using invivo/invitro tools to understand their role as upstream effectors of kidney disease and allo-immunity.
2. Non HLA-mismatches and renal allograft failure: Recent data has shown that focal or global non-HLA donor-recipient mismatches associate with renal allograft outcomes. Here we examined global non-HLA mismatches by quantifying these in every donor-recipient pair in a scale of 0-1 using proportion of identity-by-descent (piBD). We showed that such a score independently associates with allograft survival via the development of early allograft fibrosis especially vascular intimal lesions or Cv-score. Based on these data, (a) we are applying bioinformatic approaches to dissect loci and regions of interest (b) identify potential implicated mechanisms based on genetic architecture (c) validate using a murine model of global non MHC mismatches. This work has significant implications for allocation, risk stratification and potential targeted therapeutics. We identify novel mechanisms by which donor-recipient "mismatches" impact transplant outcomes. One such leading candidate is the region of LIMS1-GCC2 on chromosome 2, where complex mechanisms involving gene expression regulation underlie association of specific loci with graft loss.
Coauthors
Selected Publications
- A large-scale retrospective study enabled deep-learning based pathological assessment of frozen procurement kidney biopsies to predict graft loss and guide organ utilizationYi Z, Xi C, Menon M, Cravedi P, Tedla F, Soto A, Sun Z, Liu K, Zhang J, Wei C, Chen M, Wang W, Veremis B, Garcia-Barros M, Kumar A, Haakinson D, Brody R, Azeloglu E, Gallon L, O'Connell P, Naesens M, Shapiro R, Colvin R, Ward S, Salem F, Zhang W. A large-scale retrospective study enabled deep-learning based pathological assessment of frozen procurement kidney biopsies to predict graft loss and guide organ utilization. Kidney International 2023, 105: 281-292. PMID: 37923131, PMCID: PMC10892475, DOI: 10.1016/j.kint.2023.09.031.
- Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survivalSun Z, Zhang Z, Banu K, Gibson I, Colvin R, Yi Z, Zhang W, De Kumar B, Reghuvaran A, Pell J, Manes T, Djamali A, Gallon L, O'Connell P, He J, Pober J, Heeger P, Menon M. Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival. Journal Of Clinical Investigation 2023, 133: e170420. PMID: 37676733, PMCID: PMC10617779, DOI: 10.1172/jci170420.
- Nonpodocyte Roles of APOL1 Variants: An Evolving ParadigmPell J, Nagata S, Menon M. Nonpodocyte Roles of APOL1 Variants: An Evolving Paradigm. Kidney360 2023, 4: e1325-e1331. PMID: 37461136, PMCID: PMC10550003, DOI: 10.34067/kid.0000000000000216.
- HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagyChen M, Menon M, Wang W, Fu J, Yi Z, Sun Z, Liu J, Li Z, Mou L, Banu K, Lee S, Dai Y, Anandakrishnan N, Azeloglu E, Lee K, Zhang W, Das B, He J, Wei C. HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy. Nature Communications 2023, 14: 4297. PMID: 37463911, PMCID: PMC10354075, DOI: 10.1038/s41467-023-40086-3.
- Comparative evaluation of glomerular morphometric techniques reveals differential technical artifacts between focal segmental glomerulosclerosis and normal glomeruliReghuvaran A, Lin Q, Basgen J, Banu K, Shi H, Vashist A, Pell J, Perinchery S, He J, Moledina D, Wilson F, Menon M. Comparative evaluation of glomerular morphometric techniques reveals differential technical artifacts between focal segmental glomerulosclerosis and normal glomeruli. Physiological Reports 2023, 11: e15688. PMID: 37423891, PMCID: PMC10329935, DOI: 10.14814/phy2.15688.
- WCN23-0470 BAC-transgenic mice show a novel T-cell intrinsic role for FSGS-associated APOL1 risk-variants in T-cell activationPell J, Reghuvaran A, Nagata S, Banu K, He J, Craft J, Shi H, Chernova I, Ishibe S, Menon M. WCN23-0470 BAC-transgenic mice show a novel T-cell intrinsic role for FSGS-associated APOL1 risk-variants in T-cell activation. Kidney International Reports 2023, 8: s392-s393. DOI: 10.1016/j.ekir.2023.02.882.
- Allograft tissue under the microscope: only the beginningVirmani S, Rao A, Menon M. Allograft tissue under the microscope: only the beginning. Current Opinion In Organ Transplantation 2023, 28: 126-132. PMID: 36787238, PMCID: PMC10214011, DOI: 10.1097/mot.0000000000001052.
- Walking the Line Between Antidonor and Antiviral Immunity: A Potential Role for BelataceptGunasekaran D, Pell J, Menon M. Walking the Line Between Antidonor and Antiviral Immunity: A Potential Role for Belatacept. Kidney International Reports 2022, 8: 1-3. PMID: 36644356, PMCID: PMC9832058, DOI: 10.1016/j.ekir.2022.11.005.
- Blood Transcriptomes of SARS-CoV-2–Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to SeveritySun Z, Zhang Z, Banu K, Azzi YA, Reghuvaran A, Fredericks S, Planoutene M, Hartzell S, Kim Y, Pell J, Tietjen G, Asch W, Kulkarni S, Formica R, Rana M, Maltzman JS, Zhang W, Akalin E, Heeger PS, Cravedi P, Menon MC. Blood Transcriptomes of SARS-CoV-2–Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity. Journal Of The American Society Of Nephrology 2022, 33: 2108-2122. PMID: 36041788, PMCID: PMC9678030, DOI: 10.1681/asn.2022010125.
- Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 TrialHricik D, Armstrong B, Alhamad T, Brennan D, Bromberg J, Bunnapradist S, Chandran S, Fairchild R, Foley D, Formica R, Gibson I, Kesler K, Kim SJ, Mannon R, Menon M, Newell K, Nickerson P, Odim J, Poggio E, Sung R, Shapiro R, Tinckam K, Vincenti F, Heeger P. Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial. Journal Of The American Society Of Nephrology 2022, 34: 145-159. PMID: 36195441, PMCID: PMC10101585, DOI: 10.1681/asn.2022040454.
- Cellular recovery after prolonged warm ischaemia of the whole bodyAndrijevic D, Vrselja Z, Lysyy T, Zhang S, Skarica M, Spajic A, Dellal D, Thorn SL, Duckrow RB, Ma S, Duy PQ, Isiktas AU, Liang D, Li M, Kim SK, Daniele SG, Banu K, Perincheri S, Menon MC, Huttner A, Sheth KN, Gobeske KT, Tietjen GT, Zaveri HP, Latham SR, Sinusas AJ, Sestan N. Cellular recovery after prolonged warm ischaemia of the whole body. Nature 2022, 608: 405-412. PMID: 35922506, PMCID: PMC9518831, DOI: 10.1038/s41586-022-05016-1.
- Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving ParadigmsJethwani P, Rao A, Bow L, Menon MC. Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms. Frontiers In Immunology 2022, 13: 822353. PMID: 35432337, PMCID: PMC9012490, DOI: 10.3389/fimmu.2022.822353.
- Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodesZhang Z, Sun Z, Fu J, Lin Q, Banu K, Chauhan K, Planoutene M, Wei C, Salem F, Yi Z, Liu R, Cravedi P, Cheng H, Hao K, O’Connell P, Ishibe S, Zhang W, Coca SG, Gibson IW, Colvin RB, He J, Heeger PS, Murphy B, Menon MC. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. Journal Of Clinical Investigation 2021, 131 PMID: 34499625, PMCID: PMC8592534, DOI: 10.1172/jci146643.
- Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsiesYi Z, Salem F, Menon MC, Keung K, Xi C, Hultin S, Haroon Al Rasheed MR, Li L, Su F, Sun Z, Wei C, Huang W, Fredericks S, Lin Q, Banu K, Wong G, Rogers NM, Farouk S, Cravedi P, Shingde M, Smith RN, Rosales IA, O'Connell PJ, Colvin RB, Murphy B, Zhang W. Deep learning identified pathological abnormalities predictive of graft loss in kidney transplant biopsies. Kidney International 2021, 101: 288-298. PMID: 34757124, PMCID: PMC10285669, DOI: 10.1016/j.kint.2021.09.028.
- AMP-Kinase mediates regulation of glomerular volume and podocyte survivalBanu K, Lin Q, Basgen JM, Planoutene M, Wei C, Reghuvaran AC, Tian X, Shi H, Garzon F, Garzia A, Chun N, Cumpelik A, Santeusanio AD, Zhang W, Das B, Salem F, LI L, Ishibe S, Cantley LG, Kaufman L, Lemley KV, Ni Z, He JC, Murphy B, Menon MC. AMP-Kinase mediates regulation of glomerular volume and podocyte survival. JCI Insight 2021, 6: e150004. PMID: 34473647, PMCID: PMC8525649, DOI: 10.1172/jci.insight.150004.
- A POINT MUTATION OF SHROOM3 PROMOTES CD206+ MACROPHAGE INFILTRATION AND KIDNEY FIBROSIS AFTER ISCHEMIA-REPERFUSION INJURYTang T, Lu B, Rogers N, Zheng G, Nicholson L, Cao Q, Menon M, Murphy B, Alexander S, Hu M, O’connell P. A POINT MUTATION OF SHROOM3 PROMOTES CD206+ MACROPHAGE INFILTRATION AND KIDNEY FIBROSIS AFTER ISCHEMIA-REPERFUSION INJURY. Transplantation 2020, 104: s166-s167. DOI: 10.1097/01.tp.0000699188.09671.c3.
- Magnetic resonance elastography vs. point shear wave ultrasound elastography for the assessment of renal allograft dysfunctionKennedy P, Bane O, Hectors SJ, Gordic S, Berger M, Delaney V, Salem F, Lewis S, Menon M, Taouli B. Magnetic resonance elastography vs. point shear wave ultrasound elastography for the assessment of renal allograft dysfunction. European Journal Of Radiology 2020, 130: 109180. PMID: 32736305, DOI: 10.1016/j.ejrad.2020.109180.
- Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosisZhang Z, Menon MC, Zhang W, Stahl E, Loza BL, Rosales IA, Yi Z, Banu K, Garzon F, Sun Z, Wei C, Huang W, Lin Q, Israni A, Keating BJ, Colvin RB, Hao K, Murphy B. Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis. Kidney International 2020, 98: 758-768. PMID: 32454123, PMCID: PMC7483801, DOI: 10.1016/j.kint.2020.04.039.
- Multiparametric magnetic resonance imaging shows promising results to assess renal transplant dysfunction with fibrosisBane O, Hectors S, Gordic S, Kennedy P, Wagner M, Weiss A, Khaim R, Yi Z, Zhang W, Delaney V, Salem F, He C, Menon MC, Lewis S, Taouli B. Multiparametric magnetic resonance imaging shows promising results to assess renal transplant dysfunction with fibrosis. Kidney International 2019, 97: 414-420. PMID: 31874802, PMCID: PMC6983343, DOI: 10.1016/j.kint.2019.09.030.
- A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute RejectionZhang W, Yi Z, Keung KL, Shang H, Wei C, Cravedi P, Sun Z, Xi C, Woytovich C, Farouk S, Huang W, Banu K, Gallon L, Magee CN, Najafian N, Samaniego M, Djamali A, Alexander SI, Rosales IA, Smith RN, Xiang J, Lerut E, Kuypers D, Naesens M, O'Connell PJ, Colvin R, Menon MC, Murphy B. A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection. Journal Of The American Society Of Nephrology 2019, 30: 1481-1494. PMID: 31278196, PMCID: PMC6683710, DOI: 10.1681/asn.2018111098.
- SHROOM3-FYN Interaction Regulates Nephrin Phosphorylation and Affects Albuminuria in AllograftsWei C, Banu K, Garzon F, Basgen JM, Philippe N, Yi Z, Liu R, Choudhuri J, Fribourg M, Liu T, Cumpelik A, Wong J, Khan M, Das B, Keung K, Salem F, Campbell KN, Kaufman L, Cravedi P, Zhang W, O'Connell PJ, He JC, Murphy B, Menon MC. SHROOM3-FYN Interaction Regulates Nephrin Phosphorylation and Affects Albuminuria in Allografts. Journal Of The American Society Of Nephrology 2018, 29: 2641-2657. PMID: 30341149, PMCID: PMC6218856, DOI: 10.1681/asn.2018060573.
- Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survivalYacoub R, Nadkarni GN, Cravedi P, He JC, Delaney VB, Kent R, Chauhan KN, Coca SG, Florman SS, Heeger PS, Murphy B, Menon MC. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney International 2017, 93: 482-490. PMID: 28965746, DOI: 10.1016/j.kint.2017.07.016.
- APOL1 G2 risk allele—clarifying nomenclatureZhang Z, Hao K, Ross MJ, Murphy B, Menon MC. APOL1 G2 risk allele—clarifying nomenclature. Kidney International 2017, 92: 518-519. PMID: 28709608, DOI: 10.1016/j.kint.2017.05.009.
- Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective studyO'Connell PJ, Zhang W, Menon MC, Yi Z, Schröppel B, Gallon L, Luan Y, Rosales IA, Ge Y, Losic B, Xi C, Woytovich C, Keung KL, Wei C, Greene I, Overbey J, Bagiella E, Najafian N, Samaniego M, Djamali A, Alexander SI, Nankivell BJ, Chapman JR, Smith RN, Colvin R, Murphy B. Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study. The Lancet 2016, 388: 983-993. PMID: 27452608, PMCID: PMC5014570, DOI: 10.1016/s0140-6736(16)30826-1.
- Temporal Trends of Mortality in Acute Ischemic Stroke in Systemic Lupus Erythematosus: A Propensity-Matched Analysis of Nationwide Inpatient Data (P2.295)Patel A, Nadkarni G, Mahajan A, Konstantinidis I, Simoes P, Benjo A, Kumar Agarwal S, Pakanati K, Menon M, Annapureddy N. Temporal Trends of Mortality in Acute Ischemic Stroke in Systemic Lupus Erythematosus: A Propensity-Matched Analysis of Nationwide Inpatient Data (P2.295). Neurology 2015, 84 DOI: 10.1212/wnl.84.14_supplement.p2.295.
- Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosisMenon MC, Chuang PY, Li Z, Wei C, Zhang W, Luan Y, Yi Z, Xiong H, Woytovich C, Greene I, Overbey J, Rosales I, Bagiella E, Chen R, Ma M, Li L, Ding W, Djamali A, Saminego M, O’Connell P, Gallon L, Colvin R, Schroppel B, He JC, Murphy B. Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis. Journal Of Clinical Investigation 2014, 125: 208-221. PMID: 25437874, PMCID: PMC4382250, DOI: 10.1172/jci76902.
Clinical Trials
Conditions | Study Title |
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Diseases of the Kidney & Urinary Tract | Exploring Metformin's Impact on Kidney Health in FSGS Patients |