Dr Richard J Lang

Senior Research Fellow - Department of Physiology

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Background

Since the 1960s, the Department of Physiology at Monash University has been an internationally recognized centre of excellence in the research of smooth muscle function.

Our Cellular Systems Physiology Group have a wide range of interests, skills and experimental techniques and forms the Monash Node of the Cellular Neurophysiology Platform of the National Neuroscience Facility, providing electrophysiological services for a number of researchers and companies.

Projects that  I am directly involved in include investigations into understanding of the processes mediating inappropriate smooth muscle contraction during failure to progress to labour, during obstruction or infection of the ureter and in the prostate with age.

Research Interests

Since the earliest descriptions of pyeloureteric peristalsis by Englemann (1869), it has been recognised that the spontaneous propagating contractions, which transport urine expressed in the kidney through the ureter to the bladder, originate within the most proximal regions of the renal pelvis and little influenced by nerves within the muscle wall.  Malfunction of this peristalsis leads to accumulation of urine in the kidney and dilation of the renal pelvis (hydronephrosis) which is one of the most common congenital abnormalities detected during prenatal ultrasound screenings. 

Obstruction of the ureteropelvic junction (UPJ) is the most frequently diagnosed cause of hydronephrosis in infants and the obstruction is mostly unilateral and partial.  In adults, hydronephrosis can arise from acute or chronic ureteral obstruction, with reflux from the bladder to the kidney during bladder infections or outlet obstructions, from the presence of kidney stones and in women, pregnancy, endometriosis, cysts of the uterus or ovaries, etc.  Paradoxically, the degree of dilatation does not always correlate with the degree of obstruction, so that hydronephrosis/hydro ureter can occur with little obstruction and high grade obstructions can cause little dilatation. 

Severe hydronephrosis in infants and adults require surgical treatments such as pyeloplasty or an endoscopic internal UPJ transsection.  Relief of UPJ obstruction results in a reduction of kidney swelling and partial return to normal kidney function within a relatively short time.  However renal histopathology never returns to normal so that patients have an permanent increased risk of developing stones, infection or hypertension. 

Nonsurgical treatments to alleviate the consequences of ureteric obstruction and  upper urinary tract remodelling have not yet been developed due to the lack of an understanding of the basic physiology or molecular mechanisms underlying healthy ureteric peristalsis, let alone the consequences of muscle wall remodelling during obstruction-induced or congenital hydronephrosis.

We have previously postulated that pyeloureteric peristalsis depends on the presence of 2 populations of potential pacemaker cells, atypical smooth muscle cells (SMC) and interstitial cells of Cajal (ICC)-like cells, whose autorhythmicity can be distinguished pharmacologically. We have developed a model of pyeloureteric pacemaking in which synchronization of atypical SMC activity in the most proximal regions of the renal pelvis creates the essential pacemaker signal that triggers action potential discharge and contraction in the muscle wall.  We are presently investigating the notion that the intrinsic activity of ICC-like cells can maintain rudimentary peristaltic waves in regions distal to a site of obstruction or surgery and dislocation from the proximal atypical SMC pacemaker drive.

Alternatively, kit-immunopositive ICC-like cells could in fact be hemopoietic or progenitor (stem) cells activated under pathological conditions to differentiate and repair the renal pelvis.  If this proves to be the case an understanding of their function could well lead to novel treatments involving the introduction of progenitor cells to reverse the effects of hydronephrosis.

Elucidation of changes in cellular functions and gene expression during congenital or obstruction-induced hydronephrosis will lead to an improved understanding of the causes of these pathologies.  This will in turn lead to the identification of potential therapeutic targets and likely proteins amenable for the development of diagnostic tools for the early detection of these pathologies, even predictive proteins that would indicate the likely effectiveness of surgical intervention.

Academic Distinctions, Awards and Funding

Australian Academy of Sciences/ Japanese Society for the Promotion of Science: Short Term Fellowship (2007)

Nagoya City University Visiting Research Professor (2008)

Nagoya City University Visiting Research Professor (2009)

Since 2003 I have received invitations to speak at 7 international and 4 national meetings and symposia. Most recently I am on the organizing committee of the symposium ‘Smooth muscle function in health & disease”, a satellite meeting of International Union of Physiological Societies (2009) in  Kyoto, Japan. 

Since 1987 I have had near continuous NHMRC or ARC funding for my research.

Diabetes Australia Research Fund. Tare Parkington Sandow Drumond Coleman Lang (2008)

NHMRC Project Grant.  Lang Hashitani Parkington Kett Remodelling of pacemaker mechanisms driving ureteric peristalsis during pelviureteric obstruction  (2008-10)

NHMRC Project Grant. Parkington Wallace Lang Jenkins Control of uterine contraction : Role of interstitial cells            (2008-10)

Publications

Lang RJ, Zoltkowski BZ, Hammer JM, Meeker WF & WendtI (2007)  Electrical characterization of interstitial cells of Cajal-like cells and smooth muscle cells isolated from the mouse ureteropelvic junction.  J Urology 177, 1573-80

Nguyen T D-T, Dey A, Lang,RJ & Exintaris B, (2007)  K⁺ channel modulation of slow wave activity in the guinea pig prostate Brit J. Pharmacol. 151, 828-36

Lang RJ, Hashitani H, Tonta MA, Parkington HC & Suzuki H (2007)  Spontaneous electrical activity and Ca²⁺ transients in typical and atypical smooth muscles and interstitial cells of Cajal-like cells of mouse renal pelvis  J Physiol 583, 1049-1068

Davidson ME & Lang RJ (2007)  Pyleoureteric peristaltic contractions in diabetic rats.  J Smooth Muscle Research  43,  145-155

Lang RJ, Hashitani H, Tonta M, Suzuki H & Parkington HC (2007)  Role of Ca²⁺ entry and Ca²⁺ stores in autorhythmicity in atypical SMCs in the mouse renal pelvis. Brit J Pharmacol 152, 1248-59

Peh GS, Lang RJ, Pera, MF & SM Hawes (2009)  CD133 expression by neural progenitors derived from human embryonic stell cells and its use for their prospective isolation.  Stem Cells & Development 18, 269-282.

Exintaris B, Nguyen T D-T, Dey A, Lam M & Lang RJ (2009)  IP₃ dependent Ca²⁺ stores and mitochondria modulate slow wave activity in the young guinea-pig prostate Brit J Pharmacology ePub Feb 2009

Nguyen T D-T, Dey A, Lang RJ & Exintaris B (2009)  alpha1-adrenoceptor modulation of spontaneous electrical waveforms in the guinea-pig prostate Eur J Pharmacol ePub Feb 2009

Dey A, Nguyen T D-T, Lang RJ & Exintaris B (2009)  Spontaneous electrical activity in aging guinea pig prostates. J Urology In Press (Accepted Dec 2008)