Manjeri A Venkatachalam, MBBS
Professor of Biochemistry, Professor - Pathology and Laboratory Medicine
Dr. Manjeri Venkatachalam's expertise is in acute renal failure, renal pathology, signal transduction, surgical pathology, chronic kidney disease, glomerular structure and function, molecular pathology of cell death.
Mechanisms of Kidney Disease Progression
Following acute kidney injury (AKI), renal tubules often become atrophic, giving rise to chronic kidney disease (CKD). The molecular basis for tubule atrophy after AKI is unclear. We found the mitochondrial number to be decreased and remaining mitochondria structurally defective in atrophic tubules. Our research is aimed to understand the mechanisms of mitochondrial malfunction and mitochondrial loss after AKI and develop strategies that promote tubule recovery after AKI. Our research showed that RRM2B, the alternate regulatory subunit of ribonucleotide reductase (RNR), the oxygen-dependent enzyme that produces deoxyribonucleotides (dNTPs), is severely reduced in kidney tubules regenerating after AKI. RRM2B is essential for the generation of dNTPs required for the synthesis and repair of mitochondrial DNA (mtDNA). Our hypothesis is that reactive oxygen species (ROS) produced within mitochondria in excess of basal levels damages mtDNA and impairs respiratory chain integrity. Misdirected electron transport further increases ROS production and enhances mtDNA damage. Reduced RRM2B and consequent diminished production of dNTPs impairs mtDNA synthesis and repair, compromising mitochondrial biogenesis and integrity. Because intact mitochondria are essential for cellular vitality, tubule cells recover poorly and become atrophic, secondarily giving rise to fibrosis. Ongoing experiments address the underpinnings of RRM2B regulation and investigate the critical role played by RRM2B in mtDNA synthesis and repair. We are using cell culture and in vivo transgenic approaches to decrease, delete or overexpress RRM2B as tools to arrive at the answers we seek.
Related Diseases: Acute Kidney Injury and chronic kidney disease
Techniques: Protein and RNA analysis, laser capture microdissection, CRISPR-Cas9 knockout, shRNA knockdown, Cre-Lox recombination to produce transgenic mice, Immunofluorescence and immunohistochemistry.
- 1962 - BS - Surgery - Calcutta Medical College and Calcutta University
- 1962 - BS - Medicine - Calcutta Medical College and Calcutta University
- 1957 - BS - Science - St Xavier's College/Calcutta University
- 9/2001 - Professor of Biochemistry - University of Texas Health Science Center, Biochemistry, San Antonio
- 9/1979 - Professor of Medicine - University of Texas Health Science Center, Medicine, San Antonio
- 8/1979 - Professor of Pathology - University of Texas Health Science Center, Pathology, San Antonio
Instruction & Training
- - Present, Post-Doctoral Student Supervision, UTHSCSA
- - Present, Post-Doctoral Student Supervision, UTHSCSA
- 1/2009 - Present, Individual Instruction, University of Texas Health Science Center at San Antonio
- 1/2000 - Present, Pathology, The University of Texas Health Science Center
Research & Grants
Funding Agency National Institutes of Health Title Pathogenesis of Tubule Atrophy and Failed Recovery After Acute Kidney Injury Status Active Period 1/2016 - 12/2019 Role Principal Investigator Grant Detail
Prajjal Kanti Singha, Nandita Mishra, Rekha Kar, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana Saikumar. Targeting LC3-SQSTM1 (p62) signaling axis to treat apoptosis-resistant and metastatic breast cancers; 2010 Jan. (AACR). Singha PK, Pandeswara S, Venkatachalam MA, Saikumar P. TMEPAI, a Novel Prognostic Marker for TGF-β Dependency of Metastatic Breast Cancers: Converts Tumor Suppressive TGF-β into a Tumor Promoter; 2010 Jan. (SABCS Annual Meeting). Saikumar P, Mikhailov VI, Mikhailova M, Venkatachalam MA, Kar R. Bax mediated release of apoptosis inducing factors requires its dissociation from the inner mitochondrial membrane; 2004 Jan. (FASEB J; vol. 18, no. 8). Saikumar P, Mikhailov VI, Mikhailova M, Venkatachalam MA. Rapid cell death in Bcl-2 overexpressing rat proximal tubule cells exposed to cold and rewarming; 2003 Jan. (J Am Soc Nephrol; vol. 14). Saikumar P, Mikhailova M, Mikhailov VI, Venkatachalam MA, Denton ML. Caspase activation through formation of protein complexes during hypoxia or ATP depletion; 2002 Jan. (FASEB J; vol. 16, no. 4). Mikhailov VI, Mikhailova M, Venkatachalam MA, Saikumar P. Bax dependent release of apoptogenic factors from mitochondria by t-Bid; 2002 Jan. (J Am Soc Nephrol; vol. 13). Mikhailova M, Mikhailov VI, Denton ML, Dong Z, Venkatachalam MA, Saikumar P. Apoptotic protein complexes in hypoxic rat kidney proximal tubule cells; 2001 Jan. (J Am Soc Nephrol; vol. 12).
Manjeri A Venkatachalam, Hui Geng, Rongpei Lan, Prajjal Singha, Pothana Saikumar, and Joel M Weinberg. Maladaptive Repair and AKI to CKD Transition. In: (Schnellmann, R. G. and Cummings, Brian S. Vol. Eds), McQueen, C (Chief Editor). Renal Toxicology, in Comprehensive Toxicology Third Edition, Vol. 14. New York, NY: Elsevier; 2018. p. 164-188.
Weinberg JM. Pericytes Preserve Capillary Integrity to Prevent Kidney Hypoxia J Am Soc Nephrol 2017 Mar;28(3):717-719. Venkatachalam MA, Weinberg JM. Fibrosis without fibroblast TGF-beta receptors? kidney international 2015 Sep;88(3):434-437. Venkatachalam MA. Could Autophagic Exhaustion Be a Final Common Pathway for Podocytopathy in FSGS? J Am Soc Nephrol 2015 May;26(5):999-1001.
Morris SM Jr,
Awad AS. l-Homoarginine supplementation prevents diabetic kidney damage Physiological Reports 2019 Sep;7(18):2-9. Lee HJ, Gonzalez O, Dick EJ Jr, Donati A, Feliers D, Goutam Ghosh C, Ross C, Venkatachalam M, Tardif SD,Kasinath BS. Marmoset as a model to study kidney changes associated with aging J Gerontol A Biol Sci Med Sci 2019 Feb;74(3):315-324. Lan, R, Geng, H, Singha, P, Saikumar P, Bottinger, EP, Weinberg, JM, Venkatachalam MA. Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI Journal of the American Society of Nephrology 2016 Nov;27(11):3356-3367. Kallingal GJ, Weinberg JM, Reis IM, Nehra A, Venkatachalam MA, Parekh DJ. Long-Term Response to Renal Ischemia in the Human Kidney After Partial Nephrectomy - Results from a Prospective Clinical Trial BJU Int 2016 May;117(5):766-774. Kar R, Mishra, N, Singha, PK, Venkatachalam MA, McEwen DG, Saikumar P. Mitochondrial remodeling following fission inhibition by 15d-PGJ2 involves molecular changes in mitochondrial fusion protein OPA1 Biochem. Biophys. Res. Commun 2010 Sep;399(4):548-554. Rongpei Lan, Hui Geng, Yoon Hwang, Pramod Mishra,
Wayne L.Skloss, Eugene A. Sprague, Pothana Saikumar, and Manjeri
. A Novel Wounding Device Suitable for Quantitative Biochemical Analysis of Wound Healing and Regeneration of Cultured Epithelium Wound Repair and Regeneration 2010 Jan;18:159-167. Kar R, Mishra N, Singha P, Venkatachalam MA and Saikumar P. Mitochondrial Remodeling Following Fission Inhibition by 15d-PGJ2 Involves Molecular Changes in Mitochondrial Fusion Protein OPA1 Biochem Biophys Res Comm 2010 Jan;399(4):548-554. Mishra N, Kar R, Singha PK, Venkatachalam MA, McEwen DG, Saikumar P. Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-Delta(12,14)-prostaglandin J2 Biochem Biophys Res Commun 2010 Jan;395(1):17-24. Kar R, Singha, PK, Venkatachalam MA, Saikumar P. A novel role of LC3 in 15-deoxy-∆12, 14 Prostaglandin J2 mediated non-autophagic cancer cell death Oncogene 2009 Jul;28(28):2556-2568. Geng, H, Lan, R, Wang, G, Siddiqi, AR, Naski MC, Brooks, AI, Barnes JL, Saikumar P, Weinberg, JM, Venkatachalam MA. Inhibition of autoregulated TGFβ signaling simultaneously enhances proliferation and differentiation of kidney epithelium and promotes repair following renal ischemia Am J Pathol 2009 Jan;174(4):1291-1308. Kar R, Singha PK, Venkatachalam MA, Saikumar P. A novel role for MAP1 LC3 in nonautophagic cytoplasmic vacuolation death of cancer cells Oncogene 2009 Jan;28(28):2556-2568. Mikhailov V, Mikhailova M, Degenhardt K, Venkatachalam MA, White E, Saikumar P. Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release J Biol Chem 2003 Jan;278(7):5367-5376. Mikhailov V, Mikhailova M, Pulkrabek DJ, Dong Z, Venkatachalam MA, Saikumar P. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane J Biol Chem 2001 Jan;276(21):18361-18374.
He L Wei Q Liu Y Liu H Sun L Peng Y Liu F Venkatachalam MA Dong Z. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms Kidney International 2017 Nov;92(5):1071-1083. Yang, Y, Song, M, Liu, Y, Liu, H, Sun, L, Peng, Y, Liu, F, Venkatachalam MA, Dong, Z. Renoprotective approaches and strategies in acute kidney injury Pharmacol Ther 2016 Jul;163:58-73. Weinberg, JM, Bienholz, A, Venkatachalam MA. The role of glycine in regulated cell death Cell Mol Life Sci pii: ASN.2015020177. [Epub ahead of print] PMID: 27000065 2016 Jun;73(11-12):2285-2308. Venkatachalam MA
Bidani AK. Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression Journal of the American Society of Nephrology 2015 Mar;26(8):1765-1776. Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, Bidani AK. Acute kidney injury: a springboard for progression in chronic kidney disease Am J Physiol Renal Physiol 2010 Jan;298(5):F1078-F1094.