Babu Padanilam

 Babu J. Padanilam
Curriculum Vitae

Ph.D. 1985, Medical College of Georgia
Specialty: Pathophysiology of Acute Ischemic Renal Injury
Major Interest: Cellular, biochemical and molecular approaches to study of acute renal injury

The major focus of the laboratory is to study the mechanisms of cellular injury and renal fibrogenesis in acute kidney injury (AKI) models.  The laboratory studies the mechanisms by which selective glycolytic inhibition occurs in the ischemic kidney proximal tubules, which is the primary cause of cellular injury and death. Studies are aimed at understanding the molecular mechanisms that regulate different forms of cell death, including apoptosis, necrosis and autophagy in various experimental models of AKI. In both patients and experimental models, although normal or near normal kidney function is regained after an ischemic episode, significant risks of long term lose of renal function and development of renal fibrosis and progression to chronic kidney disease exists.  We are currently studying the role of neural factors in the regulation of renal fibrogenesis in different models.  In addition the laboratory is interested in the mitochondrial regulation of energy homeostasis in animal models of obesity.  Further details of the different projects that are currently underway are presented below.

PROJECT 1:  REGULATION OF GLYCOLYSIS IN ISCHEMIC KIDNEYS: Ischemic renal injury (IRI), generally accepted as the major cause of AKI, results from compromised perfusion of renal tissues. Following IRI, persistent perfusion deficit exists in the outer medullary nephron segments and a metabolic switch from respiration to anaerobic glycolytic energy metabolism ensues as a last resort for ATP synthesis.  However, the glycolytic capacity is inhibited selectively in the medullary proximal straight tubules (PST).  Our studies identified poly (ADP-ribose) Polymerase-1 (PARP-1) and Tp53 inducible glycolysis and apoptosis regulator (TIGAR) to be key molecules that may inhibit glycolysis and initiate the proximal tubular damage.  This project is aimed at understanding the molecular mechanisms by which these two molecules participate in glycolytic inhibition and to determine if intervening in PARP-1 and TIGAR functions may modulate PST injury and the pathogenesis of AKI.

PROJECT 2:  REGULATION OF APOPTOSIS IN ISCHEMIC KIDNEYS:  In patients where AKI is established, the PST undergo necrotic and/or apoptotic cell death or autophagy. However, the exact mechanisms by which renal tubular cells undergo either necrotic or apoptotic form of cell death have not been well defined.  Our studies identified that the p53 target Siva to be a key regulator of apoptosis in this setting.  This project will address the mechanisms by which Siva induces apoptosis in the ischemic kidney.

PROJECT 3: PROGRAMMED NECROSIS IN AKI: Necrotic cell death is widely considered to be an unregulated process that cannot be modulated by pharmacological means as opposed to apoptosis. However, our recent studies using experimental models of AKI challenge this tenet and indicate that necrosis can be “programmed” and can be prevented by targeting the molecular components of its signaling pathways, such as the mitochondrial pore forming protein, cyclophilin D (cypD) and the nuclear DNA repair enzyme Poly (ADP)-ribose polymerase (PARP). Project 3 is aimed at addressing the mechanisms by which Ca2+, PARP-1 and cyclophilin D contribute to mitochondrial dysfunction and mitochondrial permeability to ensue necrosis in ischemic and nephrotoxic (cisplatin) kidneys. 

PROJECT 4:  NEUROREGULATION OF RENAL FIBROGENESIS:  Chronic kidney disease (CKD) is progressive, not curable, and ultimately fatal. Regardless of the disease etiology, including hypertension, diabetes and glomerulonephritis, tubulointerstitial fibrosis is the final common pathway in CKD that leads to disease progression and ultimately end stage renal disease (ESRD). Our results suggest that afferent and efferent renal nerve stimulation may be the primary mechanism and nerve derived factors play key role in the initiation of fibrogenesis and the inflammatory cascade in the kidney. Studies are in progress to understand the mechanisms by which renal innervation contribute to renal injury and chronic kidney disease.

PROJECT 5:  MITOCHONDRIAL DYSFUNCTION IN HIGH FAT DIET-INDUCED OBESITY: Our studies show that deficiency in the mitochondrial matrix protein, cyclophilin D (cypD) prevents diet-induced obesity in mice and the data are published in FEBS Letters 2011.  We are currently pursuing this project by generating tissue specific knockout for cypD using cre-loxp technology.  Further we are screening for novel small molecule inhibitors of cypD,  that are candidates for preventing diet-induced obesity and its consequences. 
Acute Kidney Injury

Recent publications:

  • Jinu Kim and Padanilam BJ. Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol. 24:229-243, 2013.  PMID: 23264683 
  • Jinu Kim and Padanilam BJ. Loss of PARP-1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction Am J Physiol Renal Physiol. 2011:F450-459. Epub 2011 May 25. PMID: 21613422. 
  • Jinu Kim, Kelly Long, Kang Tang and Babu J. Padanilam. Poly(ADP-ribose) polymerase-1 activation is required for cisplatin nephrotoxicity. Kidney International; 82:193-203,  2012. PMID:22437413
  • Kurinji Singaravelu, and Babu J. Padanilam. p53 target, Siva regulates apoptosis in ischemic kidneys. Am J Physiol, Renal Physiology. 300:F1130-1141, 2011. PMID: 21307125
  • Devalaraja-Narashimha K, Padanilam BJ. Cyclophilin D deficiency prevents diet- induced obesity in mice. FEBS Letters. 585: 677-682, 2011. PMID: 21276794