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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.

RESEARCH

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.